Compounds and methods for inhibiting JAK

ABSTRACT

Disclosed are compounds of formula (I), pharmaceutical compositions comprising such compounds and methods/uses of using the same, for example, for treating a JAK-related disorder, such as cancer, cancer cachexia or an immune disorder: 
                         
wherein
         R 1  is methyl or ethyl;   R 2  is selected from methyl, ethyl, methoxy and ethoxy;   R 3  is selected from hydrogen, chlorine, fluorine, bromine and methyl;   R 4  is selected from methyl, ethyl and —CH 2 OCH 3 ;   R 5  and R 6  are each individually methyl or hydrogen; and   R 7  is selected from methyl, ethyl, —(CH 2 ) 2 OH and —(CH 2 ) 2 OCH 3 , or a pharmaceutically acceptable salt thereof.

RELATED APPLICATIONS

This application claims the benefit of priority under 35 U.S.C. §119(e)to U.S. Provisional Patent Application No. 62/232,629, filed Sep. 25,2015, the contents of which are herein incorporated by reference intheir entirety.

BACKGROUND

The JAK (Janus-associated kinase) family consists of four non-receptortyrosine kinases, JAK1, JAK2, JAK3 and Tyk2, which play a critical rolein cytokine and growth factor mediated signal transduction (Schindler C,and Darnell J E Jr., Annu. Rev. Biochem. 1995; 64; 621-651). Cytokineand/or growth factor binding to cell-surface receptors facilitatesactivation of receptor-associated JAK kinases by autophosphorylation.Activated JAKs directly phosphorylate members of the STAT (signaltransducers and activators of transcription) family of transcriptionfactors (STAT1, 2, 3, 4, 5a, 5b and 6) promoting their translocation tothe nucleus and the transcriptional activation of target genes.

Constitutive activation (i.e., tyrosine phosphorylation) of members ofthe STAT family, in particular STAT3, has been documented in a widerange of cancers and hyperproliferative disorders, and associated withpoor prognosis in several cancers (Yu H, Jove R., Nat. Rev. Cancer 2004;4:97-105). Persistently activated STAT3 has been shown to be oncogenic(Bromberg J F, et al. Cell 1999; 98:295-303) and to drive the expressionof cellular proteins contributing to central processes in cancerprogression (survival, proliferation, invasion, angiogenesis) (Yu andJove, 2004, supra). One common mechanism of STAT3 activation in cancercells is via autocrine or paracrine stimulation of JAK/STAT3 signalingby cytokines, typically members of the interleukin-6 (IL-6) cytokinefamily (Grivennikov, S. and Karin, M. Cancer Cell 2008; 13; 7-9;Bromberg J. and Wang T C. Cancer Cell 2009; 15; 79-80). This isprimarily mediated by JAK1, the key JAK kinase responsible for STAT3activation (Guschin et al., Embo J 1995; 14; 1421-1429., Kim S M, etal., Mol. Cancer Ther. 2012; 11; 2254-2264; Song et. al., Mol. CancerTher. 2011; 10; 481-494). Inactivation of negative regulatory proteins,such as the SOCS (suppressors of cytokine signalling) or PIAS (proteininhibitor of activated STATs) proteins have also been shown to influencethe activation status of the JAK/STAT signalling pathway in cancer(Mottok et al., Blood 2007; 110; 3387-90; Ogata et al., Gastroenterology2006; 131; 179-193., Lee et al., Mol. Cancer Ther. 2006; 5; 8-19,Brantley et al., Clin. Cancer Res. 2008; 14; 4694-4704).

In addition to basal activation of JAK1/STAT3 signaling in multiplehuman tumors, the pathway has also been shown to be activated as afeedback resistance mechanism in response to inhibition of driveroncogenic pathways in cancer cells, such as the mutated epidermal growthfactor receptor (EGFR) in non-small cell lung cancer (NSCLC), or theMAPK pathway in KRAS mutant tumors (Lee et al., Cancer Cell 2014; 26;207-221; VanSchaeybroeck et al., Cell reports 2014; 7; 1940-1955). Thusinhibition of JAK1 may provide a means of potentiating the therapeuticbenefit of a variety of targeted cancer therapies.

Also, cancer cachexia is a significant contributor to increasedmortality and poor response to chemotherapy in patients with advancedcancer. Elevated levels of inflammatory cytokines, such as IL-6, whichsignal through the JAK/STAT pathway have been shown to play a causalrole, indicating the potential benefit of JAK1 inhibition inameliorating cancer cachexia.

Based on the critical role JAK1 plays in signal transduction mediated byclass II cytokine receptors, the γ_(c) receptor subunit, the gp130subunit and G-CSF, as well as its dominance in driving the activity ofthe immune-relevant γ_(c) cytokines, JAK1 inhibition may be useful intreating a number of immune disorders, such as bone marrow disorders,rheumatoid arthritis, psoriasis, Crohn's disease, lupus and multiplesclerosis.

SUMMARY

Collectively, the observations of JAKs critical role in proliferativeand immune disorders highlight broad potential for JAK inhibition as atherapeutic modality in a number of diseases and disorders. Accordingly,disclosed are compounds that are JAK inhibitors.

In one embodiment, disclosed are compounds of formula (I):

wherein

R¹ is methyl or ethyl;

R² is selected from methyl, ethyl, methoxy and ethoxy;

R³ is selected from hydrogen, chlorine, fluorine, bromine and methyl;

R⁴ is selected from methyl, ethyl and —CH₂OCH₃;

R⁵ and R⁶ are each individually methyl or hydrogen; and

R⁷ is selected from methyl, ethyl, —(CH₂)₂OH and —(CH₂)₂OCH₃, or apharmaceutically acceptable salt thereof.

In one embodiment, disclosed are pharmaceutical compositions comprisinga compound of Formula (I), or a pharmaceutically acceptable salt orsolid form thereof, and a pharmaceutically acceptable diluent, excipientor carrier.

In another embodiment, disclosed are methods of treating a JAK-relateddisorder in a subject in need thereof comprising administering to thesubject an effective amount of a compound of Formula (I), or apharmaceutically acceptable salt or solid form thereof.

In another embodiment, disclosed is a compound of Formula (I), or apharmaceutically acceptable salt or solid form thereof, for use intreating a JAK-related disorder.

In another embodiment, disclosed are pharmaceutical compositionscomprising a compound of Formula (I), or a pharmaceutically acceptablesalt or solid form thereof, for use in treating a JAK-related disorder.

In another embodiment, disclosed is the use of a compound of Formula(I), or a pharmaceutically acceptable salt or solid form thereof, in themanufacture of a medicament for treating a JAK-related disorder.

In another embodiment, disclosed are methods of treating cancer in asubject in need thereof comprising administering to the subject aneffective amount of a compound as of Formula (I), or a pharmaceuticallyacceptable salt or solid form thereof, in combination with ananti-cancer therapeutic agent, or a pharmaceutically acceptable saltthereof.

In another embodiment, disclosed is a compound of Formula (I), or apharmaceutically acceptable salt or solid form thereof, in combinationwith an anti-cancer therapeutic agent, or a pharmaceutically acceptablesalt thereof, for use in treating cancer.

In another embodiment, disclosed are pharmaceutical compositionscomprising a compound of Formula (I), or a pharmaceutically acceptablesalt or solid form thereof, in combination with an anti-cancertherapeutic agent, or a pharmaceutically acceptable salt thereof, foruse in treating cancer.

In another embodiment, disclosed is the use of a compound of Formula(I), or a pharmaceutically acceptable salt or solid form thereof, incombination with an anti-cancer therapeutic agent, or a pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for treatingcancer.

In another embodiment, disclosed are methods of treating cancer cachexiain a subject in need thereof comprising administering to the subject aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt or solid form thereof.

In another embodiment, disclosed is a compound of Formula (I), or apharmaceutically acceptable salt or solid form thereof, for use intreating cancer cachexia.

In another embodiment, disclosed are pharmaceutical compositionscomprising a compound of Formula (I), or a pharmaceutically acceptablesalt or solid form thereof, for use in treating cancer cachexia.

In another embodiment, disclosed is the use of a compound of Formula(I), or a pharmaceutically acceptable salt or solid form thereof, in themanufacture of a medicament for treating cancer cachexia.

In another embodiment, disclosed are methods of treating an immunedisorder in a subject in need thereof comprising administering to thesubject an effective amount of a compound of Formula (I), or apharmaceutically acceptable salt or solid form thereof.

In another embodiment, disclosed is a compound of Formula (I), or apharmaceutically acceptable salt or solid form thereof, for use intreating an immune disorder.

In another embodiment, disclosed are pharmaceutical compositionscomprising a compound of Formula (I), or a pharmaceutically acceptablesalt or solid form thereof, for use in treating an immune disorder.

In another embodiment, disclosed is the use of a compound of Formula(I), or a pharmaceutically acceptable salt or solid form thereof, in themanufacture of a medicament for treating an immune disorder.

In another embodiment, disclosed are methods of inhibiting JAK in asubject in need thereof comprising administering to the subject aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt or solid form thereof.

In another embodiment, disclosed is a compound of Formula (I), or apharmaceutically acceptable salt or solid form thereof, for use ininhibiting JAK.

In another embodiment, disclosed are pharmaceutical compositionscomprising a compound of Formula (I), or a pharmaceutically acceptablesalt or solid form thereof, for use in inhibiting JAK.

In another embodiment, disclosed is the use of a compound of Formula(I), or a pharmaceutically acceptable salt or solid form thereof, in themanufacture of a medicament for inhibiting JAK.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the powder X-ray diffraction diagram of Form A(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide.

FIG. 2 illustrates the differential scanning calorimetry (DSC) andthermogravimetric analysis (TGA) traces of Form A(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide.

FIG. 3 illustrates the powder X-ray diffraction diagram of Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide.

FIG. 4 illustrates the differential scanning calorimetry (DSC) andthermogravimetric analysis (TGA) traces of Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide.

FIG. 5 illustrates the powder X-ray diffraction diagram of Form C(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide.

FIG. 6 illustrates the differential scanning calorimetry (DSC) andthermogravimetric analysis (TGA) traces of Form C(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide.

FIG. 7 illustrates the powder X-ray diffraction diagram of Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide.

FIG. 8 illustrates the differential scanning calorimetry (DSC) andthermogravimetric analysis (TGA) traces of Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide.

FIG. 9 illustrates the powder X-ray diffraction diagram of Form A(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt.

FIG. 10 illustrates the differential scanning calorimetry (DSC) andthermogravimetric analysis (TGA) traces of Form A(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt.

FIG. 11 illustrates the powder X-ray diffraction diagram of Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt.

FIG. 12 illustrates the differential scanning calorimetry (DSC) andthermogravimetric analysis (TGA) traces of Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt.

FIG. 13 illustrates the powder X-ray diffraction diagram of Form C(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt.

FIG. 14 illustrates the powder X-ray diffraction diagram of Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt.

FIG. 15 illustrates the powder X-ray diffraction diagram of Form E(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt.

FIG. 16 illustrates the powder X-ray diffraction diagram of(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine hydrochloride salt.

FIG. 17 illustrates the powder X-ray diffraction diagram of(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidenapadisylic salt.

FIG. 18 illustrates the powder X-ray diffraction diagram of(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidetrimesic salt.

FIG. 19 illustrates NCI-H1975 tumor volumes after treatment withvehicle, osimertinib (2.5 mg/kg QD) administered as a single agent,Example 32 (12.5 mg/kg BID, 25 m/kg BID or 50 mg/kg BID) as a singleagent, and osimertinib (2.5 mg/kg QD) in combination with Example 32(12.5 mg/kg BID, 25 mg/kg BID or 50 mg/kg BID).

represents vehicle;

represents osimertinib administered as a single agent;

represents 50 mg/kg BID Example 32 administered as a single agent;

represents 25 mg/kg BID Example 32 administered as a single agent;

represents 12.5 mg/kg BID Example 32 administered as a single agent;

represents osimertinib administered in combination with 50 mg/kg BIDExample 32;

represents osimertinib administered in combination with 25 mg/kg BIDExample 32; and

represents osimertinib administered in combination with 12.5 mg/kg BIDExample 32.

FIG. 20 illustrates body weights after treatment with vehicle,osimertinib (2.5 mg/kg QD) as a single agent, Example 32 (12.5 mg/kgBID, 25 mg/kg BID or 50 mg/kg BID) as a single agent, and osimertinib(2.5 mg/kg QD) in combination with Example 32 (12.5 mg/kg BID, 25 mg/kgBID or 50 mg/kg BID).

represents vehicle;

represents osimertinib administered as a single agent;

represents 50 mg/kg BID Example 32 administered as a single agent;

represents 25 mg/kg BID Example 32 administered as a single agent;

represents 12.5 mg/kg BID Example 32 administered as a single agent;

represents 50 mg/kg BID Example 32 administered in combination withosimertinib;

represents 25 mg/kg BID Example 32 administered in combination withosimertinib; and

represents 12.5 mg/kg BID Example 32 administered in combination withosimertinib.

FIG. 21 illustrates knockdown of pSTAT3 in NCI-H1975 tumors aftertreatment with vehicle, AZD1480 as a single agent, osimertinib (2.5mg/kg QD) as a single agent, Example 32 (12.5 mg/kg BID, 25 mg/kg BID or50 mg/kg BID) as a single agent, and osimertinib (2.5 mg/kg QD)administered in combination with Example 32 (12.5 mg/kg BID, 25 mg/kgBID or 50 mg/kg BID). ♦ represents pSTAT3 and bars represent plasmalevels of Example 32.

FIG. 22 illustrates PC-9 tumor volumes after treatment with vehicle,gefitinib (IRESSA®, 6.25 mg/kg QD) administered as a single agent andgefitinib (IRESSA®, 6.25 mg/kg QD) administered in combination withExample 32 (12.5 mg/kg BID, 50 mg/kg BID and 50 mg/kg BID dosed 2 dayson/5 days off/wk).

represents vehicle;

represents gefitinib (IRESSA®) administered as a single agent;

represents gefinitib (IRESSA®) administered in combination with 50 mg/kgBID Example 32;

represents gefitinib (IRESSA®) administered in combination with 12.5mg/kg BID Example 32; and

represents gefinitib (IRESSA®) administered in combination with 50 mg/kgBID with Example 32 dosed 2 days on/5 days off/wk.

FIG. 23 illustrates body weights after treatment with vehicle, gefitinib(IRESSA®, 6.25 mg/kg QD) administered as a single agent and gefitinib(IRESSA®, 6.25 mg/kg QD) administered in combination with Example 32(12.5 mg/kg BID, 50 mg/kg BID and 50 mg/kg 2 dosed days on/5 daysoff/wk).

represents vehicle;

represents gefitinib (IRESSA®) administered as a single agent;

represents gefinitib (IRESSA®) administered in combination with 50 mg/kgBID Example 32;

represents gefitinib (IRESSA®) administered in combination with 12.5mg/kg BID Example 32; and,

represents gefinitib (IRESSA®) administered in combination with 50 mg/kgBID Example 32 dosed 2 days on/5 days off/wk.

FIG. 24 illustrates knockdown of pSTAT3 in PC-9 tumors after treatmentwith vehicle, gefitinib (IRESSA®, 6.25 mg/kg QD) administered as asingle agent and gefitinib (IRESSA®, 6.25 mg/kg QD) administered incombination with Example 32 (12.5 mg/kg BID and 50 mg/kg BID).

FIG. 25 illustrates NCI-H1650 tumor volumes after treatment withvehicle, gefitinib (IRESSA®, 6.25 mg/kg QD) administered as a singleagent, Example 32 (25 mg/kg BID or 50 mg/kg BID) administered as asingle agent and gefitinib (IRESSA®, 6.25 mg/kg QD) administered incombination with Example 32 (25 mg/kg BID or 50 mg/kg BID).

represents vehicle;

represents gefitinib (IRESSA®) administered as a single agent;

represents 25 mg/kg BID Example 32 administered as a single agent;

represents 50 mg/kg BID Example 32 administered as a single agent;

represents gefinitib (IRESSA®) administered in combination with 25 mg/kgBID Example 32; and

represents gefinitib (IRESSA®) administered in combination with 50 mg/kgBID Example 32.

FIG. 26 illustrates body weights after treatment with vehicle, gefitinib(IRESSA®, 6.25 mg/kg QD) administered as a single agent, Example 32 (25mg/kg BID or 50 mg/kg BID) administered as a single agent and gefitinib(IRESSA®, 6.25 mg/kg D r administered in combination with Example 32 (25mg/kg BID or 50 mg/kg BID).

represents vehicle;

represents gefitinib (IRESSA®) administered as a single agent;

represents 25 mg/kg BID Example 32 administered as a single agent;

represents 50 mg/kg BID Example 32 administered as a single agent;

represents gefinitib (IRESSA®) administered in combination with 25 mg/kgBID Example 32; and

represents gefinitib (IRESSA®) administered in combination with 50 mg/kgBID Example 32.

FIG. 27 illustrates knockdown of pSTAT3 in NCI-H1650 tumors aftertreatment with vehicle, AZD1408 administered as a single agent,gefitinib (IRESSA®, 6.25 mg/kg QD) administered as a single agent,Example 32 (25 mg/kg BID or 50 mg/kg BID) administered as a single agentand gefitinib (IRESSA®, 6.25 mg/kg QD) administered in combination withExample 32 (25 mg/kg BID or 50 mg/kg BID). ♦ represents pSTAT and barsrepresent plasma levels of Example 32.

FIG. 28 illustrates LG1049 tumor volumes after treatment with vehicle (

); osimertinib (25 mg/kg QD) administered as a single agent for 28 days(

), Example 32 (25 mg/kg BID) administered as a single agent for 18 days(

); osimertinib (25 mg/kg QD) administered in combination with Example 32(25 mg/kg BID) dosed 7 days, then 3 days on/4 days off/wk until day 28 (

).

represents mice treated with the combination for 28 days, then withExample 32 (25 mg/kg BID) alone for 3 days on/4 days off/wk until theend of the study.

FIG. 29 illustrates body weights after treatment LG1049 tumor volumesafter treatment with vehicle (

), osimertinib (25 mg/kg QD) administered as a single agent for 28 days(

) Example 32 (25 mg/kg BID) administered as a single agent (

), osimertinib (25 mg/kg QD) administered in combination with Example 32(25 mg/kg BID) dosed 7 days, then 3 days on/4 days off until day 28 (

).

represents mice treated with the combination for 28 days, then withExample 32 (25 mg/kg BID) alone for 3 days on/4 days off/wk until theend of the study

FIG. 30 illustrates knockdown of pSTAT3 and pEGFR in LG1049 tumors afterfive days of treatment with vehicle, osimertinib (25 mg/kg QD)administered as a single agent, Example 32 (25 mg/kg BID) administeredas a single agent and osimertinib (25 mg/kg QD) administered incombination with Example 32 (25 mg/kg BID).

FIGS. 31A-E illustrate NCI-H1975 tumor volumes after treatment withvehicle, Example 32 administered as a single agent, osimertinibadministered as a single agent, and Example 32 administered incombination with osimertinib. FIG. 31A illustrates tumor volume overtime after continuous dosing with vehicle for 19 days (

); 50 mg/kg BID Example 32 administered as a single agent for 19 days (

); 2.5 mg/kg QD osimertinib administered as a single agent for 26 days (

); 2.5 mg/kg QD osimertinib administered in combination with 12.5 mg/kgBID Example 32 dosed for 26 days (

); and 2.5 mg/kg QD osimertinib administered in combination with 50mg/kg BID Example 32 dosed for 26 days (

). FIG. 31B illustrates tumor volume over time after dosing with vehicle(

) for 19 days; 50 mg/kg BID Example 32 administered as a single agentfor 19 days (

); 2.5 mg/kg QD osimertinib administered as a single agent for 26 days (

); 2.5 mg/kg QD osimertinib administered for 26 days in combination with25 mg/kg BID Example 32 dosed for 7 days (

); and 2.5 mg/kg QD osimertinib administered for 26 days in combinationwith 50 mg/kg BID Example 32 dosed for 7 days (

). FIG. 31C illustrates tumor volume over time after dosing with vehiclefor 19 days (

); 50 mg/kg BID Example 32 as a single agent for 19 days (

); 2.5 mg/kg QD osimertinib administered as a single agent for 26 days (

); 2.5 mg/kg QD osimertinib administered for 29 days in combination with25 mg/kg BID Example 32 dosed 7 days on/7 days off/2 wk (

); and 2.5 mg/kg QD osimertinib administered for 29 days in combinationwith 50 mg/kg BID Example 32 dosed 7 days on/7 days off/2 wk (

). FIG. 31D illustrates tumor volume over time after dosing with vehiclefor 19 days (

); 50 mg/kg BID Example 32 administered as a single agent for 19 days (

); 2.5 mg/kg QD osimertinib administered as a single agent for 26 days (

); 2.5 mg/kg QD osimertinib administered for 29 days in combination with25 mg/kg BID Example 32 dosed 4 days on/3 days off/wk (

); and 2.5 mg/kg QD osimertinib administered for 29 days in combinationwith 50 mg/kg BID Example 32 dosed for 4 days on/3 days off/wk (

). FIG. 31E illustrates tumor volume over time after dosing with vehiclefor 19 days (

); 50 mg/kg BID Example 32 for 19 days (

); 2.5 mg/kg QD osimertinib dosed for 26 days (

); 2.5 mg/kg QD osimertinib dosed for 29 days in combination with 25mg/kg BID Example 32 dosed for 2 days on/5 days off/wk (

); and 2.5 mg/kg QD osimertinib dosed for 29 days in combination with 50mg/kg BID Example 32 dosed 2 days on/5 days off/wk (

).

FIG. 32 illustrates body weight over time after treatment with vehicle,Example 32 as a single agent, osimertinib as a single agent, and Example32 in combination with osimertinib.

represents vehicle dosed for 19 days;

represents 2.5 mg/kg QD osimertinib dosed for 26 days;

represents 50 mg/kg BID Example 32 dosed for 19 days;

represents 2.5 mg/kg QD osimertinib administered in combination with12.5 mg/kg BID Example 32 dosed for 26 days;

represents 2.5 mg/kg QD osimertinib administered in combination with 50mg/kg BID Example 32 dosed for 26 days;

represents 2.5 mg/kg QD osimertinib administered for 26 days incombination with 25 mg/kg BID Example 32 dosed for 7 days;

represents 2.5 mg/kg QD osimertinib administered for 26 days incombination with 50 mg/kg BID Example 32 dosed for 7 days;

represents 2.5 mg/kg QD osimertinib administered for 29 days incombination with 50 mg/kg BID Example 32 dosed for 7 days on/7 days offfor one week;

represents 2.5 mg/kg QD osimertinib administered for 29 days incombination with 50 mg/kg BID Example 32 dosed for 7 days on/7 days offfor 2 weeks;

represents 2.5 mg/kg QD osimertinib administered for 29 days incombination with 25 mg/kg BID Example 32 dosed for 4 days on/3 days offfor one week;

represents 2.5 mg/kg QD osimertinib administered for 29 days incombination with 50 mg/kg BID Example 32 dosed for 4 days on/3 days offfor one week;

represents 2.5 mg/kg QD osimertinib administered for 29 days incombination with 25 mg/kg BID Example 32 dosed for 2 days on/5 days offfor one week; and

represents 2.5 mg/kg QD osimertinib administered for 29 days incombination with 50 mg/kg BID Example 32 dosed for 2 days on/5 days offfor one week.

DETAILED DESCRIPTION

Compounds

In one embodiment, disclosed are compounds of formula (I):

wherein

R¹ is methyl or ethyl;

R² is selected from methyl, ethyl, methoxy and ethoxy;

R³ is selected from hydrogen, chlorine, fluorine, bromine and methyl;

R⁴ is selected from methyl, ethyl and —CH₂OCH₃;

R⁵ and R⁶ are each individually methyl or hydrogen; and

R⁷ is selected from methyl, ethyl, —(CH₂)₂OH and —(CH₂)₂OCH₃, or apharmaceutically acceptable salt thereof.

In some embodiments, R¹ is methyl; R² is methoxy, ethoxy, methyl orethyl; R³ is hydrogen, fluorine methyl, chlorine or bromine; R⁴ ismethyl, ethyl or —CH₂OCH₃; R⁵ is hydrogen or methyl; R⁶ is hydrogen ormethyl; and R⁷ is methyl, —(CH₂)₂OCH₃, ethyl or —(CH₂)₂OH.

In some embodiments, R¹ is ethyl; R² is methoxy or ethoxy; R³ is methyl;R⁴ is methyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R² is methoxy; R¹ is methyl or ethyl; R³ ishydrogen, fluorine, methyl, chlorine or bromine; R⁴ is methyl, ethyl or—CH₂OCH₃; R⁵ is hydrogen or methyl; R⁶ is hydrogen or methyl; and R⁷ ismethyl, ethyl, —(CH₂)₂OCH₃ or —(CH₂)₂OH.

In some embodiments, R² is ethoxy; R¹ is methyl or ethyl; R³ isfluorine, methyl or chlorine; R⁴ is methyl, ethyl or —CH₂OCH₃; R⁵ ismethyl or hydrogen; R⁶ is methyl or hydrogen; and R⁷ is ethyl, methyl or—(CH₂)₂OCH₃.

In some embodiments, R² is methyl; R¹ is methyl; R³ is hydrogen, methylor fluorine; R⁴ is methyl, ethyl or —CH₂OCH₃; R⁵ is hydrogen; R⁶ ishydrogen and R⁷ is methyl.

In some embodiments, R² is ethyl; R¹ is methyl; R³ is methyl; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R³ is hydrogen; R¹ is methyl; R² is methoxy ormethyl; R⁴ is methyl, ethyl or —CH₂OCH₃; R⁵ is methyl or hydrogen; R⁶ ishydrogen or methyl and R⁷ is methyl, —(CH₂)₂OCH₃ or ethyl.

In some embodiments, R³ is fluorine; R¹ is methyl; R² is methoxy orethoxy; R⁴ is methyl, ethyl or —CH₂OCH₃; R⁵ is hydrogen or methyl; R⁶ ishydrogen or methyl and R⁷ is methyl, ethyl or —(CH₂)₂OCH₃.

In some embodiments, R³ is methyl; R¹ is methyl or ethyl; R² is methoxy,ethoxy, methyl or ethyl; R⁴ is methyl, ethyl or —CH₂OCH₃; R⁵ is hydrogenor methyl; R⁶ is hydrogen or methyl and R⁷ is methyl, ethyl, —(CH₂)₂OCH₃or —(CH₂)₂OH.

In some embodiments, R³ is chlorine; R¹ is methyl; R² is methoxy orethoxy; R⁴ is methyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R³ is bromine; R¹ is methyl; R² is methoxy; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R⁴ is methyl; R¹ is methyl or ethyl; R² is methoxy,ethoxy, methyl or ethyl; R³ is hydrogen, fluorine, methyl, chlorine orbromine; R⁵ is hydrogen or methyl; R⁶ is hydrogen or methyl and R⁷ ismethyl, ethyl, —(CH₂)₂OCH₃ or —(CH₂)₂OH.

In some embodiments, R⁴ is ethyl; R¹ is methyl; R² is methoxy, methyl orethoxy; R³ is methyl, hydrogen or fluorine; R⁵ is hydrogen; R⁶ ishydrogen and R⁷ is methyl.

In some embodiments, R⁴ is —CH₂OCH₃; R¹ is methyl; R² is methoxy, methylor ethoxy; R³ is methyl, fluorine or hydrogen; R⁵ is hydrogen; R⁶ ishydrogen and R⁷ is methyl.

In some embodiments, R⁵ is hydrogen; R¹ is methyl or ethyl; R² ismethoxy, ethoxy, methyl or ethyl; R³ is hydrogen, fluorine, methyl,chlorine or bromine; R⁴ is methyl, ethyl or —CH₂OCH₃; R⁶ is hydrogen ormethyl and R⁷ is methyl, ethyl, —(CH₂)₂OCH₃ or —(CH₂)₂OH.

In some embodiments, R⁵ is methyl; R¹ is methyl; R² is methoxy orethoxy; R³ is hydrogen, fluorine or methyl; R⁴ is methyl; R⁶ is hydrogenand R⁷ is methyl.

In some embodiments, R⁶ is hydrogen; R¹ is methyl or ethyl; R² ismethoxy, ethoxy, methyl or ethyl; R³ is hydrogen, fluorine, methyl,chlorine or bromine; R⁴ is methyl, ethyl or —CH₂OCH₃; R⁵ is hydrogen ormethyl and R⁷ is methyl, ethyl, —(CH₂)₂OCH₃ or —(CH₂)₂OH.

In some embodiments, R⁶ is methyl; R¹ is methyl; R² is methoxy orethoxy; R³ is fluorine, methyl or hydrogen; R⁴ is methyl; R⁵ is hydrogenand R⁷ is methyl.

In some embodiments, R⁷ is methyl; R¹ is methyl or ethyl; R² is methyl,ethyl, methoxy or ethoxy; R³ is hydrogen, chlorine, fluorine, bromine ormethyl; R⁴ is methyl, ethyl or —CH₂OCH₃; R⁵ is hydrogen or methyl; andR⁶⁻ is hydrogen or methyl.

In some embodiments, R⁷ is ethyl; R¹ is methyl; R² is methoxy or ethoxy;R³ is fluorine, methyl or hydrogen; R⁴ is methyl; R⁵ is hydrogen and R⁶is hydrogen.

In some embodiments, R⁷ is —(CH₂)₂OCH₃; R¹ is methyl; R² is methoxy orethoxy; R³ is fluorine, methyl or hydrogen; R⁴ is methyl; R⁵ is hydrogenand R⁶ is hydrogen.

In some embodiments, R⁷ is —(CH₂)₂OH; R¹ is methyl, R² is methoxy; R³ ismethyl; R⁴ is methyl; R⁵ is hydrogen and R⁶ is hydrogen.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is hydrogen; R⁴ ismethyl; R⁵ is methyl; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is fluorine; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is methyl and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is fluorine; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is —(CH₂)₂OCH₃.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is fluorine; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is ethyl.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is fluorine; R⁴ ismethyl; R⁵ is methyl; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is ethoxy; R³ is fluorine; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is ethyl.

In some embodiments, R¹ is methyl; R² is ethoxy; R³ is fluorine; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is —(CH₂)₂OCH₃.

In some embodiments, R¹ is methyl; R² is ethoxy; R³ is fluorine; R⁴ ismethyl; R⁵ is methyl; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is ethoxy; R³ is fluorine; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is methyl and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is ethoxy; R³ is fluorine; R⁴ ismethyl; R⁵ is methyl; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is methyl; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is methyl and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is methyl; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is —(CH₂)₂OH.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is methyl; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is ethyl.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is methyl; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is —(CH₂)₂OCH₃.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is methyl; R⁴ ismethyl; R⁵ is methyl; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is ethoxy; R³ is methyl; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is ethyl.

In some embodiments, R¹ is methyl; R² is ethoxy; R³ is methyl; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is —(CH₂)₂OCH₃.

In some embodiments, R¹ is methyl; R² is ethoxy; R³ is methyl; R⁴ ismethyl; R⁵ is methyl; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is ethoxy; R³ is methyl; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is methyl and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is fluorine; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is hydrogen; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is methyl and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is hydrogen; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is —(CH₂)₂OCH₃.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is hydrogen; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is ethyl.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is hydrogen; R⁴ ismethyl; R⁵ is methyl; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is hydrogen; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is methyl and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is ethoxy; R³ is methyl; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is methyl and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is hydrogen; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is methyl; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is ethoxy; R³ is methyl; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is chlorine; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is bromine; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is ethoxy; R³ is fluorine; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is ethoxy; R³ is chlorine; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methyl; R³ is hydrogen; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is methyl; R⁴ isethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is methyl; R⁴ is—CH₂OCH₃; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is hydrogen; R⁴ isethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methyl; R³ is fluorine; R⁴ isethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is fluorine; R⁴ isethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methyl; R³ is fluorine; R⁴ is—CH₂OCH₃; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is ethyl; R³ is methyl; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methyl; R³ is fluorine; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methyl; R³ is hydrogen; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is ethyl; R² is methoxy; R³ is methyl; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is ethyl; R² is ethoxy; R³ is methyl; R⁴ ismethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is methoxy; R³ is hydrogen; R⁴ is—CH₂OCH₃; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is ethoxy; R³ is methyl; R⁴ isethyl; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In some embodiments, R¹ is methyl; R² is ethoxy; R³ is methyl; R⁴ is—CH₂OCH₃; R⁵ is hydrogen; R⁶ is hydrogen and R⁷ is methyl.

In one embodiment, the compounds of formula (I) are compounds of formula(Ia):

wherein

R^(1a) is methyl or ethyl;

R^(2a) is selected from methyl, ethyl, methoxy and ethoxy;

R^(3a) is selected from hydrogen, chlorine, fluorine, bromine andmethyl;

R^(4a) is selected from methyl, ethyl and —CH₂OCH₃;

R^(5a) and R^(6a) are each individually methyl or hydrogen; and

R^(7a) is selected from methyl, ethyl, —(CH₂)₂OH and —(CH₂)₂OCH₃, or apharmaceutically acceptable salt thereof.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy, ethoxy, methylor ethyl; R^(3a) is hydrogen, fluorine methyl, chlorine or bromine;R^(4a) is methyl, ethyl or —CH₂OCH₃; R^(5a) is hydrogen or methyl;R^(6a) is hydrogen or methyl; and R^(7a) is methyl, —(CH₂)₂OCH₃, ethylor —(CH₂)₂OH.

In some embodiments, R^(1a) is ethyl; R^(2a) is methoxy or ethoxy;R^(3a) is methyl; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) ishydrogen and R^(7a) is methyl.

In some embodiments, R^(2a) is methoxy; R^(1a) is methyl or ethyl;R^(3a) is hydrogen, fluorine, methyl, chlorine or bromine; R^(4a) ismethyl, ethyl or —CH₂OCH₃; R^(5a) is hydrogen or methyl; R^(6a) ishydrogen or methyl; and R^(7a) is methyl, ethyl, —(CH₂)₂OCH₃ or—(CH₂)₂OH.

In some embodiments, R^(2a) is ethoxy; R^(1a) is methyl or ethyl; R^(3a)is fluorine, methyl or chlorine; R^(4a) is methyl, ethyl or —CH₂OCH₃;R^(5a) is methyl or hydrogen; R^(6a) is methyl or hydrogen; and R^(7a)is ethyl, methyl or —(CH₂)₂OCH₃.

In some embodiments, R^(2a) is methyl; R^(1a) is methyl; R^(3a) ishydrogen, methyl or fluorine; R^(4a) is methyl, ethyl or —CH₂OCH₃;R^(5a) is hydrogen; R^(6a) is hydrogen and R^(7a) is methyl.

In some embodiments, R^(2a) is ethyl; R^(1a) is methyl; R^(3a) ismethyl; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(3a) is hydrogen; R^(1a) is methyl; R^(2a) ismethoxy or methyl; R^(4a) is methyl, ethyl or —CH₂OCH₃; R^(5a) is methylor hydrogen; R^(6a) is hydrogen or methyl and R^(7a) is methyl,—(CH₂)₂OCH₃ or ethyl.

In some embodiments, R^(3a) is fluorine; R^(1a) is methyl; R^(2a) ismethoxy or ethoxy; R^(4a) is methyl, ethyl or —CH₂OCH₃; R^(5a) ishydrogen or methyl; R^(6a) is hydrogen or methyl and R^(7a) is methyl,ethyl or —(CH₂)₂OCH₃.

In some embodiments, R^(3a) is methyl; R^(1a) is methyl or ethyl; R^(2a)is methoxy, ethoxy, methyl or ethyl; R^(4a) is methyl, ethyl or—CH₂OCH₃; R^(5a) is hydrogen or methyl; R^(6a) is hydrogen or methyl andR^(7a) is methyl, ethyl, —(CH₂)₂OCH₃ or —(CH₂)₂OH.

In some embodiments, R^(3a) is chlorine; R^(1a) is methyl; R^(2a) ismethoxy or ethoxy; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) ishydrogen and R^(7a) is methyl.

In some embodiments, R^(3a) is bromine; R^(1a) is methyl; R^(2a) ismethoxy; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(4a) is methyl; R^(1a) is methyl or ethyl; R^(2a)is methoxy, ethoxy, methyl or ethyl; R^(3a) is hydrogen, fluorine,methyl, chlorine or bromine; R^(5a) is hydrogen or methyl; R^(6a) ishydrogen or methyl and R^(7a) is methyl, ethyl, —(CH₂)₂OCH₃ or—(CH₂)₂OH.

In some embodiments, R^(4a) is ethyl; R^(1a) is methyl; R^(2a) ismethoxy, methyl or ethoxy; R^(3a) is methyl, hydrogen or fluorine;R^(5a) is hydrogen; R^(6a) is hydrogen and R^(7a) is methyl.

In some embodiments, R^(4a) is —CH₂OCH₃; R^(1a) is methyl; R^(2a) ismethoxy, methyl or ethoxy; R^(3a) is methyl, fluorine or hydrogen;R^(5a) is hydrogen; R^(6a) is hydrogen and R^(7a) is methyl.

In some embodiments, R^(5a) is hydrogen; R^(1a) is methyl or ethyl;R^(2a) is methoxy, ethoxy, methyl or ethyl; R^(3a) is hydrogen,fluorine, methyl, chlorine or bromine; R^(4a) is methyl, ethyl or—CH₂OCH₃; R^(6a) is hydrogen or methyl and R^(7a) is methyl, ethyl,—(CH₂)₂OCH₃ or —(CH₂)₂OH.

In some embodiments, R^(5a) is methyl; R^(1a) is methyl; R^(2a) ismethoxy or ethoxy; R^(3a) is hydrogen, fluorine or methyl; R^(4a) ismethyl; R^(6a) is hydrogen and R^(7a) is methyl.

In some embodiments, R^(6a) is hydrogen; R^(1a) is methyl or ethyl;R^(2a) is methoxy, ethoxy, methyl or ethyl; R^(3a) is hydrogen,fluorine, methyl, chlorine or bromine; R^(4a) is methyl, ethyl or—CH₂OCH₃; R^(5S) is hydrogen or methyl and R^(7a) is methyl, ethyl,—(CH₂)₂OCH₃ or —(CH₂)₂OH.

In some embodiments, R^(6a) is methyl; R^(1a) is methyl; R^(2a) ismethoxy or ethoxy; R^(3a) is fluorine, methyl or hydrogen; R^(4a) ismethyl; R^(5a) is hydrogen and R^(7a) is methyl.

In some embodiments, R^(7a) is methyl; R^(1a) is methyl or ethyl; R^(2a)is methyl, ethyl, methoxy or ethoxy; R^(3a) is hydrogen, chlorine,fluorine, bromine or methyl; R^(4a) is methyl, ethyl or —CH₂OCH₃; R^(5a)is hydrogen or methyl; and R^(6a) is hydrogen or methyl.

In some embodiments, R^(7a) is ethyl; R^(1a) is methyl; R^(2a) ismethoxy or ethoxy; R^(3a) is fluorine, methyl or hydrogen; R^(4a) ismethyl; R^(5a) is hydrogen and R^(6a) is hydrogen.

In some embodiments, R^(7a) is —(CH₂)₂OCH₃; R^(1a) is methyl; R^(2a) ismethoxy or ethoxy; R^(3a) is fluorine, methyl or hydrogen; R^(4a) ismethyl; R^(5a) is hydrogen and R^(6a) is hydrogen.

In some embodiments, R^(7a) is —(CH₂)₂OH; R^(1a) is methyl, R^(2a) ismethoxy; R^(3a) is methyl; R^(4a) is methyl; R^(5a) is hydrogen andR^(6a) is hydrogen.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) ishydrogen; R^(4a) is methyl; R^(5a) is methyl; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) isfluorine; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is methyl andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) isfluorine; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is —(CH₂)₂OCH₃.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) isfluorine; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is ethyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) isfluorine; R^(4a) is methyl; R^(5a) is methyl; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is ethoxy; R^(3a) isfluorine; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is ethyl.

In some embodiments, R^(1a) is methyl; R^(2a) is ethoxy; R^(3a) isfluorine; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is —(CH₂)₂OCH₃.

In some embodiments, R^(1a) is methyl; R^(2a) is ethoxy; R^(3a) isfluorine; R^(4a) is methyl; R^(5a) is methyl; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is ethoxy; R^(3a) isfluorine; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is methyl andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is ethoxy; R^(3a) isfluorine; R^(4a) is methyl; R^(5a) is methyl; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) ismethyl; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is methyl andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) ismethyl; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is —(CH₂)₂OH.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) ismethyl; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is ethyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) ismethyl; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is —(CH₂)₂OCH₃.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) ismethyl; R^(4a) is methyl; R^(5a) is methyl; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is ethoxy; R^(3a) ismethyl; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is ethyl.

In some embodiments, R^(1a) is methyl; R^(2a) is ethoxy; R^(3a) ismethyl; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is —(CH₂)₂OCH₃.

In some embodiments, R^(1a) is methyl; R^(2a) is ethoxy; R^(3a) ismethyl; R^(4a) is methyl; R^(5a) is methyl; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is ethoxy; R^(3a) ismethyl; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is methyl andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) isfluorine; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) ishydrogen; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is methyl andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) ishydrogen; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is —(CH₂)₂OCH₃.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) ishydrogen; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is ethyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) ishydrogen; R^(4a) is methyl; R^(5a) is methyl; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) ishydrogen; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is methyl andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is ethoxy; R^(3a) ismethyl; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is methyl andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) ishydrogen; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) ismethyl; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is ethoxy; R^(3a) ismethyl; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) ischlorine; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) isbromine; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is ethoxy; R^(3a) isfluorine; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is ethoxy; R^(3a) ischlorine; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methyl; R^(3a) ishydrogen; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) ismethyl; R^(4a) is ethyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) ismethyl; R^(4a) is —CH₂OCH₃; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) ishydrogen; R^(4a) is ethyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methyl; R^(3a) isfluorine; R^(4a) is ethyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) isfluorine; R^(4a) is ethyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methyl; R^(3a) isfluorine; R^(4a) is —CH₂OCH₃; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is ethyl; R^(3a) ismethyl; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methyl; R^(3a) isfluorine; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methyl; R^(3a) ishydrogen; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is ethyl; R^(2a) is methoxy; R^(3a) ismethyl; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is ethyl; R^(2a) is ethoxy; R^(3a) ismethyl; R^(4a) is methyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is methoxy; R^(3a) ishydrogen; R^(4a) is —CH₂OCH₃; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is ethoxy; R^(3a) ismethyl; R^(4a) is ethyl; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In some embodiments, R^(1a) is methyl; R^(2a) is ethoxy; R^(3a) ismethyl; R^(4a) is —CH₂OCH₃; R^(5a) is hydrogen; R^(6a) is hydrogen andR^(7a) is methyl.

In one embodiment, the compounds of formula (I) are compounds of formula(Ib):

wherein

R^(2b) is selected from methyl, ethyl, methoxy and ethoxy;

R^(3b) is selected from hydrogen, chlorine, fluorine, bromine andmethyl; and

R^(7b) is selected from methyl, ethyl, —(CH₂)₂OH and —(CH₂)₂OCH₃, or apharmaceutically acceptable salt thereof.

In some embodiments, R^(2b) is methoxy; R^(3b) is hydrogen, fluorine,methyl, chlorine or bromine; and R^(7b) is methyl, ethyl, —(CH₂)₂OCH₃ or—(CH₂)₂OH.

In some embodiments, R^(2b) is ethoxy; R^(3b) is fluorine, methyl orchlorine; and R^(7b) is ethyl, methyl or —(CH₂)₂OCH₃.

In some embodiments, R^(2b) is methyl; R^(3b) is hydrogen, methyl orfluorine; and R^(7b) is methyl.

In some embodiments, R^(2b) is ethyl; R^(3b) is methyl; and R^(7b) ismethyl.

In some embodiments, R^(3b) is hydrogen; R^(2b) is methoxy or methyl;and R^(7b) is methyl, —(CH₂)₂OCH₃ or ethyl.

In some embodiments, R^(3b) is fluorine; R^(2b) is methoxy or ethoxy;R^(7b) is methyl, ethyl or —(CH₂)₂OCH₃.

In some embodiments, R^(3b) is methyl; R^(2b) is methoxy, ethoxy, methylor ethyl; and R^(7b) is methyl, ethyl, —(CH₂)₂OCH₃ or —(CH₂)₂OH.

In some embodiments, R^(3b) is chlorine; R^(2b) is methoxy or ethoxy;and R^(7b) is methyl.

In some embodiments, R^(3b) is bromine; R^(2b) is methoxy; and R^(7b) ismethyl.

In some embodiments, R^(7b) is methyl; R^(2b) is methyl, ethyl, methoxyor ethoxy; and R^(3b) is hydrogen, chlorine, fluorine, bromine ormethyl.

In some embodiments, R^(7b) is ethyl; R^(2b) is methoxy or ethoxy; andR^(3b) is fluorine, methyl or hydrogen.

In some embodiments, R^(7b) is —(CH₂)₂OCH₃; R^(2b) is methoxy or ethoxy;and R^(3b) is fluorine, methyl or hydrogen.

In some embodiments, R^(7b) is —(CH₂)₂OH; R^(2b) is methoxy; and R^(3a)is methyl.

In some embodiments, R^(2b) is methoxy; R^(3b) is fluorine; and R^(7b)is —(CH₂)₂OCH₃.

In some embodiments, R^(2b) is methoxy; R^(3b) is fluorine; and R^(7a)is ethyl.

In some embodiments, R^(2b) is ethoxy; R^(3b) is fluorine; and R^(7a) isethyl.

In some embodiments, R^(2b) is ethoxy; R^(3b) is fluorine; and R^(7b) is—(CH₂)₂OCH₃.

In some embodiments, R^(2b) is methoxy; R^(3b) is methyl; and R^(7b) is—(CH₂)₂OH.

In some embodiments, R^(2b) is methoxy; R^(3b) is methyl; and R^(7b) isethyl.

In some embodiments, R^(2b) is methoxy; R^(3b) is methyl; and R^(7b) is—(CH₂)₂OCH₃.

In some embodiments, R^(2b) is ethoxy; R^(3b) is methyl; and R^(7b) isethyl. In some embodiments, R^(2b) is ethoxy; R^(3b) is methyl; andR^(7b) is —(CH₂)₂OCH₃.

In some embodiments, R^(2b) is methoxy; R^(3b) is fluorine; and R^(7b)is methyl.

In some embodiments, R^(2b) is methoxy; R^(3b) is hydrogen; and R^(7b)is —(CH₂)₂OCH₃.

In some embodiments, R^(2b) is methoxy; R^(3b) is hydrogen; and R^(7b)is ethyl.

In some embodiments, R^(2b) is methoxy; R^(3b) is hydrogen; and R^(7b)is methyl.

In some embodiments, R^(2b) is methoxy; R^(3b) is methyl; and R^(7b) ismethyl.

In some embodiments, R^(2b) is ethoxy; R^(3b) is methyl; and R^(7b) ismethyl.

In some embodiments, R^(2b) is methoxy; R^(3b) is chlorine; and R^(7b)is methyl.

In some embodiments, R^(2b) is methoxy; R^(3b) is bromine; and R^(7b) ismethyl.

In some embodiments, R^(2b) is ethoxy; R^(3b) is fluorine; and R^(7b) ismethyl.

In some embodiments, R^(2b) is ethoxy; R^(3b) is chlorine; and R^(7b) ismethyl.

In some embodiments, R^(2b) is methyl; R^(3b) is hydrogen; and R^(7b) ismethyl.

In some embodiments, R^(2b) is ethyl; R^(3b) is methyl; and R^(7b) ismethyl.

In some embodiments, R^(2b) is methyl; R^(3b) is fluorine; and R^(7b) ismethyl.

In some embodiments, R^(2b) is methyl; R^(3b) is hydrogen; and R^(7b) ismethyl.

In some embodiments, disclosed are the compounds of Table 1, or apharmaceutically acceptable salt thereof:

TABLE 1 Example No. Chemical Structure Name Example 1

(2R)-2-[(2S)-2,4- dimethylpiperazin-1- yl]-N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4- yl)amino]pyrimidin-4-yl}- 1H-indol-7-yl)propanamideExample 2

(2R)-2-[(3R)-3,4- dimethylpiperazin-1-yl]-N-(3-{5-fluoro-2-[(3-methoxy-1- methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}- 1H-indol-7-yl)propanamide Example 3

(2R)-N-(3-{5-fluoro-2- [(3-methoxy-1-methyl- 1H-pyrazol-4-yl)amino]pyrimidin-4-yl}- 1H-indol-7-yl)-2-[4-(2-methoxyethyl)piperazin-1- yl]propanamide Example 4

(2R)-2-(4-ethylpiperazin- 1-yl)-N-(3-{5-fluoro-2-[(3-methoxy-1-methyl-1H- pyrazol-4-yl)amino] pyrimidin-4-yl}-1H-indol-7-yl)propanamide Example 5

(2R)-2-[(3S)-3,4- dimethylpiperazin-1- yl]-N-(3-{5-fluoro-2-[(3-methoxy-1- methyl-1H-pyrazol-4- yl)amino]pyrimidin-4-yl}-1H-indol-7- yl)propanamide Example 6

(2R)-2-[(2R)-3,4- dimethylpiperazin-1- yl]-N-(3-{5-fluoro-2-[(3-methoxy-1- methyl-1H-pyrazol-4- yl)amino]pyrimidin-4-yl}-1H-indol-7- yl)propanamide Example 7a

(2R)-2-[(2S)-2,4- dimethylpiperazin-1- yl]-N-(3-{5-fluoro-2-[(3-methoxy-1-methyl- 1H-pyrazol-4- yl)amino]pyrimidin-4-yl}-1H-indol-7- yl)propanamide Example 7b

(2S)-2-[(2S)-2,4- dimethylpiperazin-1- yl]-N-(3-{5-fluoro-2-[(3-methoxy-1- methyl-1H-pyrazol-4- yl)amino]pyrimidin-4-yl}-1H-indol-7- yl)propanamide Example 8

(2R)-N-(3-{2-[(3- ethoxy-1-methyl-1H- pyrazol-4-yl)amino]-5-fluoropyrimidin-4-yl}- 1H-indol-7-yl)-2- (4-ethylpiperazin-1-yl)propanamide Example 9

(2R)-N-(3-{2-[(3- ethoxy-1-methyl-1H- pyrazol-4-yl)amino]-5-fluoropyrimidin-4-yl}- 1H-indol-7-yl)-2- [4-(2-methoxyethyl)piperazin-1-yl]propanamide Example 10a

(2R)-2-[(2S)-2,4- dimethylpiperazin-1- yl]-N-(3-{2-[(3-ethoxy-1-methyl-1H-pyrazol- 4-yl)amino]-5- fluoropyrimidin-4-yl}-1H-indol-7-yl)propanamide Example 10b

(2S)-2-[(2S)-2,4- dimethylpiperazin-1- yl]-N-(3-{2-[(3-ethoxy-1-methyl-1H-pyrazol- 4-yl)amino]-5- fluoropyrimidin-4-yl}-1H-indol-7-yl)propanamide Example 11a

(2R)-2-[(3S)-3,4- dimethylpiperazin-1- yl]-N-(3-{2-[(3-ethoxy-1-methyl-1H- pyrazol-4-yl)amino]-5- fluoropyrimidin-4-yl}-1H-indol-7-yl)propanamide Example 11b

(2S)-2-[(3S)-3,4- dimethylpiperazin-1- yl]-N-(3-{2-[(3-ethoxy-1-methyl-1H- pyrazol-4-yl)amino]-5- fluoropyrimidin-4- yl}-1H-indol-7-yl)propanamide Example 12

(2R)-2-[(2R)-2,4- dimethylpiperazin-1- yl]-N-(3-{2-[(3-ethoxy-1-methyl-1H-pyrazol- 4-yl)amino]-5- fluoropyrimidin-4-yl}-1H-indol-7-yl)propanamide Example 13

(2R)-2-[(3R)-3,4- dimethylpiperazin-1- yl]-N-(3-{2-[(3-ethoxy-1-methyl-1H- pyrazol-4-yl)amino]-5- fluoropyrimidin-4-yl}-1H-indol-7-yl)propanamide Example 14

(2R)-2-[(3S)-3,4- dimethylpiperazin-1- yl]-N-(3-{2-[(3-methoxy-1-methyl-1H- pyrazol-4-yl)amino]-5- methylpyrimidin-4-yl}-1H-indol-7-yl)propanamide Example 15

(2R)-2-[4-(2- hydroxyethyl)piperazin- 1-yl]-N-(3-{2-[(3-methoxy-1-methyl- 1H-pyrazol-4-yl) amino]-5-methylpyrimidin-4-yl}-1H-indol-7- yl)propanamide Example 16

(2R)-2-(4-ethylpiperazin- 1-yl)-N-(3- {2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl) amino]-5- methylpyrimidin-4-yl}-1H-indol-7-yl)propanamide Example 17

(2R)-2-[4-(2- methoxyethyl)piperazin- 1-yl]-N-(3-{2-[(3-methoxy-1-methyl-1H- pyrazol-4-yl)amino]-5- methylpyrimidin-4-yl}-1H-indol-7- yl)propanamide Example 18

(2R)-2-[(3R)-3,4- dimethylpiperazin-1- yl]-N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol- 4-yl)amino]-5- methylpyrimidin-4-yl}- 1H-indol-7-yl)propanamide Example 19

(2R)-2-[(2S)-2,4- dimethylpiperazin-1- yl]-N-(3-{2-[(3-methoxy-1-methyl-1H- pyrazol-4-yl)amino]-5- methylpyrimidin-4- yl}-1H-indol-7-yl)propanamide Example 20

(2R)-N-(3-{2-[(3- ethoxy-1-methyl-1H- pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}- 1H-indol-7-yl)- 2-(4-ethylpiperazin-1-yl)propanamide Example 21

(2R)-N-(3-{2-[(3- ethoxy-1-methyl-1H- pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}- 1H-indol-7-yl)- 2-[4-(2-methoxyethyl)piperazin-1- yl]propanamide Example 22

(2R)-2-[(2S)-2,4- dimethylpiperazin-1- yl]-N-(3-{2-[(3-ethoxy-1-methyl-1H- pyrazol-4-yl)amino]-5- methylpyrimidin-4-yl}- 1H-indol-7-yl)propanamide Example 23

(2R)-2-[(2R)-2,4- dimethylpiperazin-1- yl]-N-(3-{2-[(3-ethoxy-1-methyl-1H- pyrazol-4-yl)amino]-5- methylpyrimidin-4- yl}-1H-indol-7-yl)propanamide Example 24

(2R)-2-[(3R)-3,4- dimethylpiperazin-1- yl]-N-(3-{2-[(3-ethoxy-1-methyl-1H- pyrazol-4-yl)amino]-5- methylpyrimidin-4- yl}-1H-indol-7-yl)propanamide Example 25

(2R)-N-(3-{5-Fluoro- 2-[(3-methoxy-1- methyl-1H-pyrazol-4-yl)amino]pyrimidin-4- yl}-1H-indol-7- yl)-2-(4-methylpiperazin-1-yl)propanamide Example 26

(2R)-2-[(3S)-3,4- dimethylpiperazin-1- yl]-N-(3-{2-[(3-methoxy-1-methyl-1H- pyrazol-4-yl)amino] pyrimidin-4-yl}-1H-indol-7-yl)propanamide Example 27

(2R)-2-[4-(2- methoxyethyl)piperazin- 1-yl]-N-(3-{2-[(3-methoxy-1-methyl- 1H-pyrazol-4-yl)amino] pyrimidin-4-yl}-1H-indol-7-yl)propanamide Example 28

(2R)-2-(4- ethylpiperidin-1-yl)-N-(3- {2-[(3-methoxy-1-methyl-1H-pyrazol- 4-yl)amino]pyrimidin- 4-yl}-1H-indol-7-yl)propanamide Example 29

(2R)-2-[(2R)-2,4- dimethylpiperazin-1- yl]-N-(3-{2-[(3-methoxy-1-methyl-1H- pyrazol-4-yl)amino] pyrimidin-4-yl}-1H-indol-7-yl)propanamide Example 30

(2R)-2-[(3R)-3,4- dimethylpiperazin-1- yl]-N-(3-{2-[(3-methoxy-1-methyl-1H- pyrazol-4-yl)amino] pyrimidin-4-yl}-1H-indol-7-yl)propanamide Example 31a

(2R)-2-[(3S)-3,4- dimethylpiperazin-1- yl]-N-(3-{2-[(3-ethoxy-1-methyl-1H- pyrazol-4-yl)amino]-5- methylpyrimidin-4-yl}- 1H-indol-7-yl)propanamide Example 31b

(2S)-2-[(3S)-3,4- dimethylpiperazin-1- yl]-N-(3-{2-[(3-ethoxy-1-methyl-1H- pyrazol-4-yl)amino]-5- methylpyrimidin-4-yl}- 1H-indol-7-yl)propanamide Example 32

(2R)-N-(3-{2-[(3- methoxy-1-methyl- 1H-pyrazol-4-yl)amino] pyrimidin-4-yl}-1H-indol-7-yl)-2-(4- methylpiperazin-1- yl)propanamide Example 33

(2S)-N-(3-{2-[(3- methoxy-1-methyl- 1H-pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}- 1H-indol-7-yl)- 2-(4-methylpiperazin-1-yl)propanamide Example 34

(2R)-N-(3-{2-[(3- Methoxy-1-methyl- 1H-pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}- 1H-indol-7-yl)- 2-(4-methylpiperazin-1-yl)propanamide Example 35

(2R)-N-(3-{2-[(3- ethoxy-1-methyl-1H- pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}- 1H-indol-7-yl)- 2-(4-methylpiperazin-1-yl)propanamide Example 36

(2R)-N-(3-{5-chloro- 2-[(3-methoxy-1- methyl-1H-pyrazol-4-yl)amino]pyrimidin-4- yl}-1H-indol-7-yl)-2- (4-methylpiperazin-1-yl)propanamide Example 37

(2R)-N-(3-{5-bromo- 2-[(3-methoxy-1- methyl-1H-pyrazol-4-yl)amino]pyrimidin-4- yl}-1H-indol-7-yl)-2- (4-methylpiperazin-1-yl)propanamide Example 38

(2R)-2-[(2R)-2,4- dimethylpiperazin-1- yl]-N-(3-{2-[(3-methoxy-1-methyl-1H- pyrazol-4-yl)amino]-5- methylpyrimidin-4- yl}-1H-indol-7-yl)propanamide Example 39

(2R)-N-(3-{2-[(3- ethoxy-1-methyl-1H- pyrazol-4-yl)amino]-5-fluoropyrimidin-4-yl}- 1H-indol-7-yl)-2- (4-methylpiperazin-1-yl)propanamide Example 40

(2R)-N-(3-{5-chloro- 2-[(3-ethoxy-1- methyl-1H-pyrazol-4-yl)amino]pyrimidin-4- yl}-1H-indol-7-yl)-2- (4-methylpiperazin-1-yl)propanamide Example 41

(2R)-N-(3-{2-[(1,3- dimethyl-1H-pyrazol- 4-yl)amino]-5-methylpyrimidin-4-yl}- 1H-indol-7-yl)- 2-(4-methylpiperazin-1-yl)propanamide Example 42

(2S)-N-(3-{2- [(1,3-dimethyl-1H- pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}- 1H-indol-7-yl)- 2-(4-methylpiperazin-1-yl)propanamide Example 43

(2S)-N-(3-{2-[(3- Methoxy-1-methyl- 1H-pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}- 1H-indol-7-yl)-2-(4- methylpiperazin-1-yl)butanamide Example 44

(2R)-N-(3-{2-[(3- Methoxy-1-methyl- 1H-pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}- 1H-indol-7-yl)- 2-(4-methylpiperazin-1-yl)butanamide Example 45

(2R)-3-methoxy-N- (3-{2-[(3-methoxy- 1-methyl-1H-pyrazol- 4-yl)amino]-5-methylpyrimidin-4-yl}- 1H-indol-7-yl)- 2-(4-methylpiperazin-1-yl)propanamide Example 46

(2S)-3-methoxy-N- (3-{2-[(3-methoxy- 1-methyl-1H-pyrazol- 4-yl)amino]-5-methylpyrimidin-4-yl}- 1H-indol-7-yl)- 2-(4-methylpiperazin-1-yl)propanamide Example 47

(2R)-N-(3-{2-[(3- Methoxy-1-methyl- 1H-pyrazol-4-yl) amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4- methylpiperazin-1- yl)butanamide Example 48

(2S)-N-(3-{2-[(3- Methoxy-1-methyl- 1H-pyrazol-4-yl) amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4- methylpiperazin-1- yl)butanamide Example 49

(2R)-N-(3-{2-[(1,3- dimethyl-1H-pyrazol- 4-yl)amino]-5-fluoropyrimidin-4-yl}- 1H-indol-7-yl)-2- (4-methylpiperazin-1-yl)butanamide Example 50

(2S)-N-(3-{2- [(1,3-dimethyl-1H- pyrazol-4-yl)amino]-5-fluoropyrimidin-4-yl}- 1H-indol-7-yl)-2- (4-methylpiperazin-1-yl)butanamide Example 51

(2R)-N-(3-{5-fluoro- 2-[(3-methoxy-1- methyl-1H-pyrazol-4-yl)amino]pyrimidin- 4-yl}-1H-indol-7- yl)-2-(4-methylpiperazin-1-yl)butanamide Example 52

(2S)-N-(3-{5-fluoro- 2-[(3-methoxy-1- methyl-1H-pyrazol-4-yl)amino]pyrimidin- 4-yl}-1H-indol-7- yl)-2-(4-methylpiperazin-1-yl)butanamide Example 53

(2R)-N-(3-{2- [(1,3-dimethyl-1H- pyrazol-4-yl)amino]-5-fluoropyimidin-4-yl}- 1H-indol-7-yl)-3-methoxy- 2-(4-methylpiperazin-1-yl)propanamide Example 54

(2S)-N-(3-{2-[(1,3- dimethyl-1H-pyrazol- 4-yl)amino]-5-fluoropyrimidin-4-yl}- 1H-indol-7-yl)-3- methoxy-2-(4-methylpiperazin-1- yl)propanamide Example 55

(2R)-N-(3-{2-[(3- ethyl-1-methyl-1H- pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}- 1H-indol-7-yl)- 2-(4-methylpiperazin-1-yl)propanamide Example 56

(2R)-N-(3-{2-[(1,3- dimethyl-1H-pyrazol- 4-yl)amino]-5-fluoropyrimidin-4-yl}- 1H-indol-7-yl)-2- (4-methylpiperazin-1-yl)propanamide Example 57

(2R)-N-(3-{2- [(1,3-dimethyl-1H- pyrazol-4-yl)amino] pyrimidin-4-yl}-1H-indol-7-yl)-2- (4-methylpiperazin- 1-yl)propanamide Example 58

(2R)-N-(3-{2-[(1- ethyl-3-methoxy-1H- pyrazol-4-yl)amino]-5-methylpyrimidin-4- yl}-1H-indol-7-yl)- 2-(4-methylpiperazin-1-yl)propanamide Example 59

(2R)-N-(3-{2-[(3- ethoxy-1-ethyl-1H- pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}- 1H-indol-7-yl)- 2-(4-methylpiperazin-1-yl)propanamide Example 60

(2R)-3-Methoxy-N- (3-{2-[(3-methoxy- 1-methyl-1H-pyrazol-4-yl)amino]pyrimidin- 4-yl}-1H-indol-7- yl)-2-(4-methylpiperazin-1-yl)propanamide Example 61

(2S)-3-Methoxy-N- (3-{2-[(3-methoxy- 1-methyl-1H-pyrazol-4-yl)amino]pyrimidin- 4-yl}-1H-indol-7- yl)-2-(4-methylpiperazin-1-yl)propanamide Example 62

(2R)-N-(3-{2-[(3- ethoxy-1-methyl-1H- pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}- 1H-indol-7-yl)- 2-(4-methylpiperazin-1-yl)butanamide Example 63

(2S)-N-(3-{2-[(3- ethoxy-1-methyl-1H- pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}- 1H-indol-7-yl)- 2-(4-methylpiperazin-1-yl)butanamide Example 64

(2R)-N-(3-{2-[(3- ethoxy-1-methyl-1H- pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}- 1H-indol-7-yl)-3-methoxy- 2-(4-methylpiperazin-1-yl)propanamide Example 65

(2S)-N-(3-{2-[(3- ethoxy-1-methyl-1H- pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}- 1H-indol-7-yl)-3-methoxy- 2-(4-methylpiperazin-1-yl)propanamide

In one aspect, the disclosed compounds are obtainable by any processdescribed in the Examples. In one embodiment, the disclosed are theintermediate compounds described in the Examples.

The language “pharmaceutically acceptable salt” includes acid additionor base salts that retain the biological effectiveness and properties ofthe compounds of Formula (I), (Ia), (Ib) and Table 1 and, whichtypically are not biologically or otherwise undesirable. In many cases,Formula (I), (Ia), (Ib) and Table 1 are capable of forming acid and/orbase salts by virtue of the presence of amino and/or carboxyl groups orgroups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, napadisylate, naphthoate,napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate,palmitate, palmoate, phosphate/hydrogen phosphate/dihydrogen phosphate,polygalacturonate, propionate, stearate, succinate, subsalicylate,tartrate, tosylate, trimesate and trifluoroacetate salts. Inorganicacids from which salts can be derived include, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like. Organic acids from which salts can be derived include, forexample, acetic acid, propionic acid, glycolic acid, oxalic acid, maleicacid, malonic acid, succinic acid, fumaric acid, tartaric acid, trimesicacid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid,napadisylic acid, ethanesulfonic acid, toluenesulfonic acid,trifluoroacetic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases. Inorganic bases from which salts can bederived include, for example, ammonium salts and metals from columns Ito XII of the periodic table. In certain embodiments, the salts arederived from sodium, potassium, ammonium, calcium, magnesium, iron,silver, zinc, and copper; particularly suitable salts include ammonium,potassium, sodium, calcium and magnesium salts. Organic bases from whichsalts can be derived include, for example, primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, basic ion exchange resins, and thelike. Certain organic amines include isopropylamine, benzathine,cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazineand tromethamine.

The pharmaceutically acceptable salts of the compounds Formula (I),(Ia), (Ib) and Table 1 can be synthesized from a basic or acidic moiety,by conventional chemical methods. Generally, such salts can be preparedby reacting free acid forms of these compounds with a stoichiometricamount of the appropriate base (such as Na⁺, Ca²⁺, Mg²⁺, or K⁺hydroxide, carbonate, bicarbonate or the like), or by reacting free baseforms of these compounds with a stoichiometric amount of the appropriateacid. Such reactions are typically carried out in water or in an organicsolvent, or in a mixture of the two. Generally, use of non-aqueous medialike ether, ethyl acetate, ethanol, isopropanol, or acetonitrile isdesirable, where practicable. Lists of additional suitable salts can befound, e.g., in “Remington's Pharmaceutical Sciences,” 20th ed., MackPublishing Company, Easton, Pa., (1985); and in “Handbook ofPharmaceutical Salts: Properties, Selection, and Use” by Stahl andWermuth (Wiley-VCH, Weinheim, Germany, 2002).

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms for the compounds of Formula (I),(Ia), (Ib) and Table 1. Isotopically labeled compounds have structuresdepicted by the formulas given herein except that one or more atoms arereplaced by an atom having a selected atomic mass or mass number.Examples of isotopes that can be incorporated into the compounds ofFormula (I), (Ia), (Ib) and Table 1 include isotopes of hydrogen,carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as²H, ³H, ¹¹C, ¹³C, ¹⁴C ¹⁵N, ¹⁶F, ³¹P, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. Thecompounds of Formula (I), (Ia), (Ib) and Table 1 may include variousisotopically labeled compounds into which radioactive isotopes, such as²H, ³H, ¹³C and ¹⁴C, are present. Isotopically labeled compounds offormula (I), (Ia) and (Ib) can generally be prepared by conventiontechniques known to those skilled in the art or by processes analogousto those described in the accompanying Examples using appropriateisotopically labeled reagents in place of the non-labeled reagentspreviously employed.

The compounds of formula (I), (Ia), (Ib) and Table 1 may have differentisomeric forms. The language “optical isomer” or “stereoisomer” refersto any of the various stereoisomeric configurations which may exist fora given compound of formula (I), (Ia), (Ib) and Table 1. It isunderstood that a substituent may be attached at a chiral center of acarbon atom and, therefore, the disclosed compounds include enantiomers,diastereomers and racemates. The term “enantiomer” includes pairs ofstereoisomers that are non-superimposable mirror images of each other. A1:1 mixture of a pair of enantiomers is a racemic mixture. The term isused to designate a racemic mixture where appropriate. The terms“diastereomers” or “diastereoisomers” include stereoisomers that have atleast two asymmetric atoms, but which are not mirror images of eachother. The absolute stereochemistry is specified according to theCahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, thestereochemistry at each chiral center may be specified by either R or S.Resolved compounds whose absolute configuration is unknown can bedesignated (+) or (−) depending on the direction (dextro- orlevorotatory) which they rotate plane polarized light at the wavelengthof the sodium D line. Certain of the compounds of Formula (I), (Ia),(Ib) and Table 1 contain one or more asymmetric centers or axes and maythus give rise to enantiomers, diastereomers or other stereoisomericforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)-. The present disclosure is meant to include all such possibleisomers, including racemic mixtures, optically pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques well known in the art, such as chiral HPLC.

Solid Forms

In some embodiments, disclosed are solid forms of the compounds ofFormula (I), (Ia) and (Ib), or a pharmaceutically acceptable saltthereof. The term “solid form” includes polymorphs, crystalline salts,solvates, hydrates and amorphous forms of the compounds of Formula (I),(Ia) and (Ib). In some embodiments, disclosed are solid forms of(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide,or a pharmaceutically acceptable salt thereof. The term “polymorph”includes crystalline materials that have the same chemical compositionbut different molecular packing. The term language “crystalline salt”includes crystalline structures with the same chemical materials, butincorporating acid or base addition salts within the molecular packingof the crystalline structure. The term “solvate” includes crystallinestructures of the same chemical material, but incorporating molecules ofsolvent within the molecular packing of the crystalline structure. Theterm “hydrates” includes crystalline structures of the same chemicalmaterial, but incorporating molecules of water within the molecularpacking of the crystalline structure. The language “amorphous form”includes compounds of the same molecular material but without themolecular order of a crystalline structure (e.g., polymorph, crystallinesalt, solvate or hydrate) of the same molecular material.

It is generally known that solid materials may be characterized usingconventional techniques such as X-Ray Powder Diffraction (XRPD),Differential Scanning Calorimetry (DSC), Thermal Gravimetric Analysis(TGA), Diffuse Reflectance Infrared Fourier Transform (DRIFT)spectroscopy, Near Infrared (NIR) spectroscopy, solution and/or solidstate nuclear magnetic resonance spectroscopy. The water content of suchsolid materials may be determined by Karl Fischer analysis.

The solid forms described herein provide XRPD patterns substantially thesame as the XRPD patterns shown in the Figures, and have the various2-theta (2θ) values as shown in the Tables included herein. One skilledin the art will understand that an XRPD pattern or diffractogram may beobtained which has one or more measurement errors depending on therecording conditions, such as the equipment or machine used. Similarly,it is generally known that intensities in an XRPD pattern may fluctuatedepending on measurement conditions or sample preparation as a result ofpreferred orientation. Persons skilled in the art of XRPD will furtherrealize that the relative intensity of peaks can also be affected by,for example, grains above 30 μm in size and non-unitary aspect ratios.The skilled person understands that the position of reflections can beaffected by the precise height at which the sample sits in thediffractometer, and also the zero calibration of the diffractometer. Thesurface planarity of the sample may also have a small effect.

As a result of these considerations, the diffraction pattern datapresented are not to be taken as absolute values (Jenkins, R & Snyder,R. L. ‘Introduction to X-Ray Powder Diffractometry’ John Wiley & Sons1996; Bunn, C. W. (1948), ‘Chemical Crystallography’, Clarendon Press,London; Klug, H. P. & Alexander, L. E. (1974), ‘X-Ray DiffractionProcedures’). It should also be understood that the solid forms embodiedherein are not limited to those that provide XRPD patterns that areidentical to the XRPD pattern shown in the Figures, and any solid formsproviding XRPD patterns substantially the same as those shown in theFigures fall within the scope of the corresponding embodiment. A personskilled in the art of XRPD is able to judge the substantial identity ofXRPD patterns. Generally, a measurement error of a diffraction angle inan XRPD is approximately 2θ (±0.2°), and such degree of a measurementerror should be taken into account when considering the X-ray powderdiffraction pattern in the Figures and when reading data contained inthe Tables included herein.

A person skilled in the art also understands that the value or range ofvalues observed in a particular compound's DSC thermogram will showvariation between batches of different purities. Therefore, whilst forone compound the range may be small, for others the range may be quitelarge. Generally, a measurement error of a diffraction angle in DSCthermal events is approximately plus or minus 5° C., and such degree ofa measurement error should be taken into account when considering theDSC data included herein. TGA thermograms show similar variations, suchthat a person skilled in the art recognizes that measurement errorsshould be taken into account when judging substantial identity of TGAthermograms.

In some embodiments, disclosed is a solid form of(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide,or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed is an amorphous form of(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide,or a pharmaceutically acceptable salt thereof.

Form A

In some embodiments, disclosed is Form A(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide.

In some embodiments, Form A(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 20 (±0.20)selected from the peaks listed in Table 17.

In some embodiments, Form A(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern substantially similar to FIG. 1.

In some embodiments, Form A(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas a DSC thermogram comprising an endotherm with a desolvation onset atabout 110° C. and a peak at about 113° C.

In some embodiments, Form A(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas a DSC thermogram substantially similar to FIG. 2.

In some embodiments, Form A(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas a TGA thermogram exhibiting a mass loss of about 7.8% upon heatingfrom about 25° C. to about 150° C.

In some embodiments, Form A2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas a TGA thermogram substantially similar to FIG. 2.

Form B

In some embodiments, disclosed is Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide.

In some embodiments, Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 20 (±0.20)selected from the peaks listed in Table 18.

In some embodiments, Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern substantially similar to FIG. 3.

In some embodiments, Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas a DSC thermogram comprising an endotherm with a desolvation onset atabout 112° C. and a peak at about 117° C.

In some embodiments, Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas a DSC thermogram substantially similar to FIG. 4.

In some embodiments, Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas a TGA thermogram exhibiting a mass loss of about 10.0% upon heatingfrom about 25° C. to about 200° C.

In some embodiments, Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas a TGA thermogram substantially similar to FIG. 4.

Form C

In some embodiments, disclosed is Form C(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide.

In some embodiments, Form C(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from the peaks listed in Table 19.

In some embodiments, Form C(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern substantially similar to FIG. 5.

In some embodiments, Form C(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas a DSC thermogram comprising an endotherm with a desolvation onset atabout 112° C. and a peak at about 114° C.

In some embodiments, Form C(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas a DSC thermogram substantially similar to FIG. 6.

In some embodiments, Form C(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas a TGA thermogram exhibiting a mass loss of about 9.2% upon heatingfrom about 25° C. to about 175° C.

In some embodiments, Form C(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas a TGA thermogram substantially similar to FIG. 6.

Form D

In some embodiments, disclosed is Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)at about 21.8°.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)at about 6.4°.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)at about 16.6°.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)at about 8.9°.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)at about 8.1.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from about 21.8° and 6.4°.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from about 21.8° and 16.6°.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from about 21.8° and 8.9°.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from about 21.8° and 8.1°.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from about 6.4° and 16.6°.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from about 6.4° and 8.9°.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from about 6.4° and 8.1.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from about 16.6° and 8.9°.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from about 16.6° and 8.1°.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from about 8.1° and 8.9°.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from about 21.8°, 6.4° and 16.6°.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from about 21.8°, 6.4° and 8.9°.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from about 21.8°, 6.4° and 8.1°.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from about 21.8°, 16.6° and 8.9°.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from about 21.8°, 16.6° and 8.1°.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from about 21.8°, 8.90 and 8.1°.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from about 16.6°, 8.90 and 8.10.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from about 21.8°, 6.4°, 16.6° and 8.9°.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from about 21.8°, 6.4°, 16.6° and 8.10.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from about 6.4°, 16.6°, 8.9° and 8.1°.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from about 21.8°, 6.4°, 16.6°, 8.9° and 8.10.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern comprising at least one peak expressed as 2θ (±0.20)selected from the peaks listed in Table 20.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas an XRPD pattern substantially similar to FIG. 7.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas a DSC thermogram comprising an endotherm with a desolvation onset atabout 116° C. and a peak at about 119° C.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas a DSC thermogram substantially similar to FIG. 8.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas a TGA thermogram exhibiting a mass loss of about 8.0% upon heatingfrom about 25° C. to about 200° C.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehas a TGA thermogram substantially similar to FIG. 8.

Form A-Saccharine Salt

In some embodiments, disclosed is Form A(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt.

In some embodiments, Form A(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt has an XRPD pattern comprising at least one peakexpressed as 2θ (±0.20) selected from the peaks listed in Table 21.

In some embodiments, Form A(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt has an XRPD pattern substantially similar to FIG. 9.

In some embodiments, Form A(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt has a DSC thermogram comprising an endotherm with amelting point onset at about 163° C. and a peak at about 169° C.

In some embodiments, Form A(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt has a DSC thermogram substantially similar to FIG. 10.

In some embodiments, Form A(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt has a TGA thermogram exhibiting a mass loss of about3.1% upon heating from about 25° C. to about 150° C.

In some embodiments, Form A(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt has a TGA thermogram substantially similar to FIG. 10.

Form B-Saccharine Salt

In some embodiments, disclosed is Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt.

In some embodiments, Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt has an XRPD pattern comprising at least one peakexpressed as 2θ (±0.20) selected from the peaks listed in Table 22.

In some embodiments, Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt has an XRPD pattern substantially similar to FIG. 11.

In some embodiments, Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt has a DSC thermogram comprising an endotherm with abroad desolvation peak at about 53° C. and two endotherm events with anonset at about 153° C. and a peak at 162° C. and an onset at about 176°C. and a peak at about 182° C.

In some embodiments, Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt has a DSC thermogram substantially similar to FIG. 12.

In some embodiments, Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt has a TGA thermogram exhibiting a mass loss of about2.7% upon heating from about 25° C. to about 100° C.

In some embodiments, Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt has a TGA thermogram substantially similar to FIG. 12.

Form C-Saccharine Salt

In some embodiments, disclosed is Form C(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt.

In some embodiments, Form C(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt has an XRPD pattern comprising at least one peakexpressed as 20 (±0.20) selected from the peaks listed in Table 23.

In some embodiments, Form C(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt has an XRPD pattern substantially similar to FIG. 13.

Form D-Saccharine Salt

In some embodiments, disclosed is Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt has an XRPD pattern comprising at least one peakexpressed as 20 (±0.20) selected from the peaks listed in Table 24.

In some embodiments, Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt has an XRPD pattern substantially similar to FIG. 14.

Form E-Saccharine Salt

In some embodiments, disclosed is Form E(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt.

In some embodiments, Form E(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt has an XRPD pattern comprising at least one peakexpressed as 2θ (±0.20) selected from the peaks listed in Table 25.

In some embodiments, Form E(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt has an XRPD pattern substantially similar to FIG. 15.

Hydrochloride Saccharine Salt

In some embodiments, disclosed is(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehydrochloride saccharine salt.

In some embodiments,(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehydrochloride saccharine salt has an XRPD pattern comprising at leastone peak expressed as 2θ (±0.20) selected from the peaks listed in Table26.

In some embodiments,(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehydrochloride saccharine salt has an XRPD pattern substantially similarto FIG. 16.

Napadisylic Salt

In some embodiments, disclosed is(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidenapadisylic salt.

In some embodiments,(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehydrochloride napadisylic salt has an XRPD pattern comprising at leastone peak expressed as 2θ (±0.20) selected from the peaks listed in Table27.

In some embodiments,(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidenapadisylic salt has an XRPD pattern substantially similar to FIG. 17.

Trimesic Salt

In some embodiments, disclosed is(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidetrimesic salt.

In some embodiments,(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidehydrochloride trimesic salt has an XRPD pattern comprising at least onepeak expressed as 2θ (±0.20) selected from the peaks listed in Table 28.

In some embodiments,(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidetrimesic salt has an XRPD pattern substantially similar to FIG. 18.

Pharmaceutical Compositions

In some embodiments, disclosed are pharmaceutical compositionscomprising a compound of formula (I), (Ia), (Ib) or of Table 1, and apharmaceutically acceptable excipient, carrier or diluent.

The language “pharmaceutically acceptable excipient, carrier or diluent”includes compounds, materials, compositions, and/or dosage forms whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of human beings and animals without excessivetoxicity, irritation, allergic response, or other problem orcomplication, as ascertained by one of skill in the art.

The disclosed compositions may be in a form suitable for oral use (forexample, as tablets, lozenges, hard or soft capsules, aqueous or oilysuspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example, as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example, as a finely divided powder or a liquidaerosol), for administration by insufflation (for example, as a finelydivided powder) or for parenteral administration (for example, as asterile aqueous or oily solution for intravenous, subcutaneous,intramuscular or intramuscular dosing or as a suppository for rectaldosing).

The disclosed compositions may be obtained by conventional proceduresusing conventional pharmaceutical excipients well known in the art.Thus, compositions intended for oral use may contain, for example, oneor more coloring, sweetening, flavoring and/or preservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate; granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate; andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearanceusing conventional coating agents and procedures well known in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oroil, such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form or in the form of nano or micronized particles togetherwith one or more suspending agents, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents such as lecithin or condensation productsof an alkylene oxide with fatty acids (for example polyoxethylenestearate), or condensation products of ethylene oxide with long chainaliphatic alcohols, for example heptadecaethyleneoxycetanol, orcondensation products of ethylene oxide with partial esters derived fromfatty acids and a hexitol such as polyoxyethylene sorbitol monooleate,or condensation products of ethylene oxide with long chain aliphaticalcohols, for example heptadecaethyleneoxycetanol, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand a hexitol such as polyoxyethylene sorbitol monooleate, orcondensation products of ethylene oxide with partial esters derived fromfatty acids and hexitol anhydrides, for example polyethylene sorbitanmonooleate. The aqueous suspensions may also contain one or morepreservatives such as ethyl or propyl p-hydroxybenzoate; anti-oxidantssuch as ascorbic acid; coloring agents; flavoring agents; and/orsweetening agents such as sucrose, saccharine or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as arachis oil, olive oil, sesame oil or coconutoil or in a mineral oil such as liquid paraffin. The oily suspensionsmay also contain a thickening agent such as beeswax, hard paraffin orcetyl alcohol. Sweetening agents such as those set out above, andflavoring agents may be added to provide a palatable oral preparation.These compositions may be preserved by the addition of an anti-oxidantsuch as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavoring and coloring agents,may also be present.

The pharmaceutical compositions may also be in the form of oil-in-wateremulsions. The oily phase may be a vegetable oil, such as olive oil orarachis oil, or a mineral oil, such as for example liquid paraffin or amixture of any of these. Suitable emulsifying agents may be, forexample, naturally-occurring gums such as gum acacia or gum tragacanth,naturally-occurring phosphatides such as soya bean, lecithin, an estersor partial esters derived from fatty acids and hexitol anhydrides (forexample sorbitan monooleate) and condensation products of the saidpartial esters with ethylene oxide such as polyoxyethylene sorbitanmonooleate. The emulsions may also contain sweetening, flavoring andpreservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavoring and/or coloring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Compositions for administration by inhalation may be in the form of aconventional pressurized aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For further information on Routes of Administration andDosage Regimes the reader is referred to Chapter 25.3 in Volume 5 ofComprehensive Medicinal Chemistry (Corwin Hansch; Chairman of EditorialBoard), Pergamon Press 1990.

The compounds of Formula (I), (Ia), (Ib) and Table 1 may be administeredonce, twice, three times a day or as many times in a 24 hour period asmedically necessary. One of skill in the art would readily be able todetermine the amount of each individual dose based on the subject. Insome embodiments, the compounds of Formula (I), (Ia), (Ib) or Table 1are administered in one dosage form. In some embodiments, the compoundsof formula (I), (Ia), (Ib) or Table are administered in multiple dosageforms.

Methods

In one aspect, disclosed are methods for treating a JAK-related disorderin a subject in need thereof, comprising administering to the subject aneffective amount of a compound of Formula (I), (Ia), (Ib) or Table 1, ora pharmaceutically acceptable salt or solid form thereof.

In one aspect, disclosed is a compound of Formula (I), (Ia), (Ib) orTable 1, or a pharmaceutically acceptable salt or solid form thereof,for use in treating a JAK-related disorder.

In one aspect, disclosed is the use of a compound of Formula (I), (Ia),(Ib) or Table 1, or a pharmaceutically acceptable salt or solid formthereof, in the manufacture of a medicament for treating a JAK-relateddisorder.

In one aspect, disclosed are pharmaceutical compositions comprising acompound of Formula (I), (Ia), (Ib) or Table 1, or a pharmaceuticallyacceptable salt or solid form thereof, for use in treating a JAK-relateddisorder.

The language “JAK-related disorder” includes cancer, cancer cachexia andimmune disorders.

The term “cancer” includes cancers with: (i) an EGFR-related etiologysuch as non-small cell lung cancer (NSCLC), head and neck: squamous cellcancer (HNSCC) and colorectal cancer; (ii) and activating RAS familymutations such as NSCLC, pancreatic cancer, colorectal cancer, prostatecancer, melanoma, thyroid cancer, bladder cancer, cholangiocarcinoma,and leukemia; (iii) a HER2 amplification or mutation such as breastcancer, gastric cancer, lung cancer; (iv) an ALK gene activation such aslung cancer, breast cancer, colorectal cancer, diffuse large B-celllymphoma, anaplastic large cell lymphoma; (v) a MET amplification ormutation such as NSCLC, gastric cancer, colorectal cancer, papillaryrenal cell carcinoma; and (vi) an FGFR-related etiology such as breastcancer, gastric cancer, endometrial cancer, lung cancer. In someembodiments, the cancer is pancreatic cancer, gastrointestinal cancer,breast cancer, a gynecological cancer (e.g., ovarian cancer or cervicalcancer), bladder cancer, SCHN, non-small cell lung cancer or small celllung cancer. In some embodiments, the cancer has metastasized.

In one aspect, disclosed are methods for treating cancer in a subject inneed thereof comprising administering to the subject an effective amountof a compound of Formula (I), (Ia), (Ib), or Table 1, or apharmaceutically acceptable salt or solid form thereof in combinationwith an anti-cancer therapeutic agent, or a pharmaceutically acceptablesalt thereof.

In one aspect, disclosed is a compound of Formula (I), (Ia), (Ib) orTable 1, or a pharmaceutically acceptable salt or solid form thereof incombination with anti-cancer therapeutic agent, or a pharmaceuticallyacceptable salt thereof, for use in treating a cancer.

In one aspect, disclosed is the use of a compound of Formula (I), (Ia),(Ib) or Table 1, or a pharmaceutically acceptable salt or solid formthereof, in combination with an anti-cancer therapeutic agent, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for treating cancer.

In one aspect, disclosed are pharmaceutical compositions comprising acompound of Formula (I), (Ia), (Ib) or Table 1, or a pharmaceuticallyacceptable salt or solid form thereof, in combination with ananti-cancer therapeutic agent, or a pharmaceutically acceptable saltthereof, for use in treating cancer.

The language “in combination with” includes administering the compoundof Formula (I), (Ia), (Ib) or Table 1, or a pharmaceutically acceptablesalt thereof, and the anti-cancer therapeutic agent, or pharmaceuticallyacceptable salt thereof, sequentially, separately or simultaneously. Insome aspects, the compound of Formula (I), (Ia), (Ib) or Table 1, or apharmaceutically acceptable salt thereof, and the anti-cancertherapeutic agent, or pharmaceutically acceptable salt thereof, areadministered in the same formulation, for example, in a fixed doseformulation. In some embodiments, the compound of Formula (I), (Ia),(Ib) or Table 1, or a pharmaceutically acceptable salt thereof, and theanti-cancer therapeutic agent, or pharmaceutically acceptable saltthereof, are administered in separate formulations, and are administeredat substantially the same time, sequentially or separately. In someembodiments, the compound of Formula (I), (Ia), (Ib) or Table 1, orpharmaceutically acceptable salt thereof, is administered for one day,two days, three days, four days, five days, six days, seven days, eightdays, nine days, ten days, 11 days, 12 days, 13 days, 14 days, threeweeks or one month in a row. In some embodiments, compound of Formula(I), (Ia), (Ib) or Table 1, or pharmaceutically acceptable salt thereof,is administered intermittently, for example, for 7 days followed by a 7day clearance period (e.g., 7 days on/7 days off), for 1 day followed bya 6 day clearance period (e.g., 1 day on/6 days off), for 2 daysfollowed by a 5 day clearance period (2 days on/5 days off), for 3 daysfollowed by a 4 day clearance period (e.g., 3 days on/4 days off), for 4days followed by a 3 day clearance period (e.g., 4 days on/3 days off),for 5 days followed by a 2 day clearance period (5 days on/2 days off),or for 6 days followed by a 1 day clearance period (6 days on/1 dayoff).

The language “anti-cancer therapeutic agent” includes, for example, EGFRinhibitors, MAPK pathway inhibitors, Raf inhibitors, HER2 inhibitors,FGFR inhibitors, antimetabolites, alkylating agents and antimitoticagents, and pharmaceutically acceptable salts thereof.

In some embodiments, a compound of Formula (I), (Ia), (Ib) or Table 1 isadministered in combination with one or more EGFR inhibitors. Examplesof EGFR inhibitors include EGFR antibodies, ABX-EGF, anti-EGFRimmunoliposomes, EGF-vaccine, EMD-7200, ERBITUX® (cetuximab), HR3, IgAantibodies, IRESSA® (gefitinib), TARCEVA® (erlotinib or OSI-774), TP-38,EGFR fusion protein, TYKERB® (lapatinib), TAGRISSO™ (osimertinib orAZD9291), GILOTRIF® (afatinib), CO-1686, WZ4002, PD153035, PF 00299804and the like. In some embodiments, a compound of Formula (I), (Ia), (Ib)or Table 1 is administered in combination with osimertinib. In someembodiments, a compound of Formula (I), (Ia), (Ib) or Table 1 isadministered in combination with gefitinib.

In some embodiments, a compound of Formula (I), (Ia), (Ib) or Table 1 isadministered in combination with one or more MAPK pathway inhibitors.MAPK pathway inhibitors include MEK inhibitors such as Selumetinib,Mekinist® (trametinib), Cobimetinib, PD0325901, Pimasertib, MEK162,Refametinib and the like; Raf and B-Raf inhibitors which includevemurafenib, dabrafenib, Encorafenib (LGX818) and the like.

In some embodiments, a compound of Formula (I), (Ia), (Ib) or Table 1 isadministered in combination with one or more HER2 inhibitors. HER2inhibitors include CP-724-714, CI-1033 (canertinib), HERCEPTIN®(trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4, petuzumab), TAK-165,GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166, dHER2 (HER2vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecific antibody,B7.her2IgG3, AS HER2 bifunctional bispecific antibodies, mAB AR-209, mAB2B-1 and the like.

In some embodiments, a compound of Formula (I), (Ia), (Ib) or Table 1 isadministered in combination with one or more ALK inhibitors. ALKinhibitors include crizotinib, ceritinib, and the like.

In some embodiments, a compound of Formula (I), (Ia), (Ib) or Table 1 isadministered in combination with one or more FGFR inhibitors. FGFRinhibitors include AZD4547, BJG398, Dovitinib, Lucitanib, MGFR1877S,FP-1039 and the like.

In some embodiments, a compound of Formula (I), (Ia), (Ib) or Table 1 isadministered in combination with one or more MET inhibitors. METinhibitors include Savolitinib, Onartuzumab, Rilotumumab, Cabozantinib,Tivantinib, LY2875358, Ficlatuzumab, Foretinib, Crizotinib, INC280,AMG337, MSC2156119J and the like

In some embodiments, a compound of Formula (I), (Ia), (Ib) or Table 1 isadministered in combination with one or more antimetabolites.Antimetabolites include ALIMTA® (pemetrexed disodium, LY231514, MTA),5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine),clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside,decitabine, deferoxamine, doxifluridine, eflornithine, EICAR(5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide), enocitabine,ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination withleucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN® (melphalan),mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolicacid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,pemextred, raltitrexed, Ribavirin, triapine, trimetrexate, S-1,tiazofurin, tegafur, TS-1, vidarabine, UFT and the like.

In some embodiments, a compound of Formula (I), (Ia), (Ib) or Table 1 isadministered in combination with one or more alkylating agents.Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone,bendamustine, brostallicin, busulfan, cisplatin, carboplatin,carboquone, carmustine (BCNU), chlorambucil, CLORETAZINE® (laromustine,VNP 40101M), cyclophosphamide, decarbazine, estramustine, fotemustine,glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide,melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustardN-oxide, nitrosoureas, oxaliplatin, ranimustine, temozolomide, thiotepa,TREANDA® (bendamustine), treosulfan, rofosfamide and the like.

In some embodiments, a compound of Formula (I), (Ia), (Ib) or Table 1 isadministered in combination with one or more antimitotic agents.Antimitotic agents include batabulin, epothilone D (KOS-862),N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940(109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO(synthetic epothilone) and the like.

The language “cancer cachexia” includes a syndrome with symptoms thatincludes host tissue wasting, anorexia, asthenia and abnormal hostintermediary metabolism. In some embodiments, the subject suffering fromcancer cachexia has pancreatic cancer or an upper gastrointestinalcancer, for example, esophageal cancer, stomach cancer, gastric cancer,liver cancer, gall bladder cancer, neuroendocrine cancer or Barrett'sesophagus. In some embodiments, the subject suffering from cancercachexia has terminal cancer.

In one aspect, disclosed are methods for treating cancer cachexia in asubject in need thereof comprising administering to the subject aneffective amount of a compound of Formula (I), (Ia), (Ib), or Table 1,or a pharmaceutically acceptable salt or solid form thereof.

In one aspect, disclosed is a compound of Formula (I), (Ia), (Ib) orTable 1, or a pharmaceutically acceptable salt or solid form thereof,for use in treating cancer cachexia.

In one aspect, disclosed is the use of a compound of Formula (I), (Ia),(Ib) or Table 1, or a pharmaceutically acceptable salt or solid formthereof, in the manufacture of a medicament for treating cancercachexia.

In one aspect, disclosed are pharmaceutical compositions comprising acompound of Formula (I), (Ia), (Ib) or Table 1, or a pharmaceuticallyacceptable salt or solid form thereof, for use in treating cancercachexia.

The language “immune disorder” includes, for example, bone marrowdisorders (e.g., myelofibrosis and polycythemia vera), rheumatoidarthritis, psoriasis, irritable bowel disease (IBD), Crohn's disease,lupus, multiple sclerosis, asthma, autoimmune thyroid disorders (e.g.,Hashimoto's thyroiditis, Graves' disease or post-partum thyroiditis),ulcerative colitis, Alopecia areata, vitiligo and myositis.

In one aspect, disclosed are methods for treating an immune disorder ina subject in need thereof comprising administering to the subject aneffective amount of a compound of Formula (I), (Ia), (Ib), or Table 1,or a pharmaceutically acceptable salt or solid form thereof.

In one aspect, disclosed is a compound of Formula (I), (Ia), (Ib) orTable 1, or a pharmaceutically acceptable salt or solid form thereof,for use in treating an immune disorder.

In one aspect, disclosed is the use of a compound of Formula (I), (Ia),(Ib) or Table 1, or a pharmaceutically acceptable salt or solid formthereof, in the manufacture of a medicament for treating an immunedisorder.

In one aspect, disclosed are pharmaceutical compositions comprising acompound of Formula (I), (Ia), (Ib) or Table 1, or a pharmaceuticallyacceptable salt or solid form thereof, for use in treating an immunedisorder.

In one aspect, disclosed are methods for inhibiting JAK in a subject inneed thereof, comprising administering to the subject an effectiveamount of a compound of Formula (I), (Ia), (Ib) or Table 1, or apharmaceutically acceptable salt or solid form thereof.

In one aspect, disclosed is a compound of Formula (I), (Ia), (Ib) orTable 1, or a pharmaceutically acceptable salt or solid form thereof,for use in inhibiting JAK.

In one aspect, disclosed is the use of a compound of Formula (I), (Ia),(Ib) or Table 1, or a pharmaceutically acceptable salt or solid formthereof, in the manufacture of a medicament for inhibiting JAK.

In one aspect, disclosed are pharmaceutical compositions comprising acompound of Formula (I), (Ia), (Ib) or Table 1, or a pharmaceuticallyacceptable salt or solid form thereof, for use in inhibiting JAK.

The term “JAK” includes a family of Janus kinases that areintracellular, nonreceptor tyrosine kinases that transducecytokine-mediated signals via the JAK-STAT pathway. The term JAKincludes JAK1, JAK2 and JAK3. In some embodiments, the compounds ofFormula (I), (Ia) and (Ib) are selective inhibitors of JAK1, JAK2 and/orJAK3. The language “selective inhibitor” includes compounds that have agreater inhibitory effect (as demonstrated, for example, by a lowerIC₅₀) for one or two of the JAK family members over the other JAK familymembers. For example, a JAK1-selective inhibitor exhibits greaterinhibitory effect on JAK1 over JAK2 and JAK3; a JAK2-selective inhibitorexhibits a greater inhibitory effect on JAK2 over JAK1 and JAK3; aJAK3-selective inhibitor exhibits a greater inhibitory effect on JAK3over JAK1 and JAK2; a JAK1/2-selective inhibitor exhibits a greaterinhibitory effect on JAK1 and JAK2 over JAK3; a JAK1/3-selectiveinhibitor exhibits a greater inhibitory effect on JAK1 and JAK3 overJAK2; and a JAK2/3-selective inhibitor exhibits a greater inhibitoryeffect on JAK2 and JAK3 over JAK1. In some embodiments, the compounds ofFormula (I), (Ia) and (Ib) are JAK1-selective inhibitors. In someembodiments, the compounds of Formula (I), (Ia) and (Ib) areJAK1/2-selective inhibitors.

The language “effective amount” includes an amount of a compound ofFormula (I), (Ia), (Ib) or Table 1 that will elicit a biological ormedical response in a subject, for example, the reduction or inhibitionof enzyme or protein activity related to JAK, cancer or an immunedisorder; amelioration of symptoms of cancer or an immune disorder; orthe slowing or delaying of progression of cancer or an immune disorder.In some embodiments, the language “effective amount” includes the amountof a compound of Formula (I), (Ia), (Ib) or Table 1, that whenadministered to a subject, is effective to at least partially alleviate,inhibit, and/or ameliorate cancer or an immune disorder or inhibit JAK,and/or reduce or inhibit the growth of a tumor or proliferation ofcancerous cells in a subject.

The term “subject” includes warm blooded mammals, for example, primates,dogs, cats, rabbits, rats, and mice. In some embodiments, the subject isa primate, for example, a human. In some embodiments, the subject issuffering from cancer or an immune disorder. In some embodiments, thesubject is in need of treatment (e.g., the subject would benefitbiologically or medically from treatment). In some embodiments, thesubject is suffering from cancer cachexia. In some embodiments, thesubject is suffering from cancer. In some embodiments, the subject issuffering from cancer cachexia. In some embodiments, the subject issuffering from an immune disorder. In some embodiments, the subject mayhave elevated blood levels of inflammatory biomarkers e.g., serumsystemic C-reactive protein (CRP), IL-6, TNFa, IL-1, procalcitonin andIL-8. In some embodiments, the subject may be suffering from a highSTAT3-positive tumor. In some embodiments, the subject is suffering froma EGFR-M positive cancer (e.g., non-small cell lung cancer). In someembodiments, the EGFR-M positive cancer has a predominatelyT790M-positive mutation. In some embodiments, the EGFR-M positive cancerhas a predominately T790M-negative mutation. In some embodiments, thesubject is suffering from a KRAS mutant cancer (e.g., KRAS mutatednon-small cell lung cancer). In some embodiments, the subject issuffering from metastatic pancreatic cancer, metastatic gastrointestinalcancer, metastatic breast cancer, a metastatic gynecologic cancer (e.g.,metastatic ovarian cancer or metastatic cervical cancer), metastaticbladder cancer, metastatic squamous cell head and neck cancer (SCHN),metastatic non-small cell lung cancer, metastatic haematological cancers(e.g., non-Hodgkin's lymphoma) or metastatic small cell lung cancer. Insome embodiments, the subject suffering from cancer may show evidence ofimmune inflammation, including, for example, the presence of PDL1,interferon gamma, tumor-infiltrating leukocytes and gene expressionsignatures indicating increased type I or type II interferon signaling,abnormal levels tumor suppressive cells, such as regulatory Tlymphocytes or myeloid-derived cells, abnormal levels of granulocytes orproteins indicating the presence of granulocytes.

The language “inhibit,” “inhibition” or “inhibiting” includes a decreasein the baseline activity of a biological activity or process. In someembodiments, the compounds of Formula (I), (Ia), (Ib) or Table 1 inhibitJAK.

The language “treat,” “treating” and “treatment” includes the reductionor inhibition of enzyme or protein activity related to JAK, cancer or animmune disorder in a subject, amelioration of one or more symptoms of acancer or an immune disorder in a subject, or the slowing or delaying ofprogression of cancer or an immune disorder in a subject. The language“treat,” “treating” and “treatment” also includes the reduction orinhibition of the growth of a tumor or proliferation of cancerous cellsin a subject.

EXAMPLES

Aspects of the present disclosure can be further defined by reference tothe following non-limiting examples, which describe in detailpreparation of certain compounds and intermediates of the presentdisclosure and methods for using compounds of the present disclosure. Itwill be apparent to those skilled in the art that many modifications,both to materials and methods, can be practiced without departing fromthe scope of the present disclosure.

Unless stated otherwise:

(i) all syntheses were carried out at ambient temperature, i.e. in therange 17 to 25° C. and under an atmosphere of an inert gas such asnitrogen unless otherwise stated;

(ii) evaporations were carried out by rotary evaporation or utilisingGenevac equipment or Biotage v10 evaporator in vacuo and work-upprocedures were carried out after removal of residual solids byfiltration;

(iii) flash chromatography purifications were performed on an automatedTeledyne Isco CombiFlash® Rf or Teledyne Isco CombiFlash® Companion®using prepacked RediSep Rf Gold™ Silica Columns (20-40 μm, sphericalparticles), GraceResolv™ Cartridges (Davisil® silica) or Silicyclecartridges (40-63 μm).

(iv) preparative chromatography was performed on a Gilson prep HPLCinstrument with UV collection; alternatively, preparative chromatographywas performed on a Waters AutoPurification HPLC-MS instrument with MS-and UV-triggered collection;

(v) chiral preparative chromatography was performed on a Gilsoninstrument with UV collection (233 injector/fraction collector, 333 &334 pumps, 155 UV detector) or a Varian Prep Star instrument (2×SD1pumps, 325 UV detector, 701 fraction collector) pump running with Gilson305 injection; alternatively, chiral preparative chromatography wasperformed on a Waters Prep 100 SFC-MS instrument with MS- andUV-triggered collection or a Thar MultiGram III SFC instrument with UVcollection.

(vi) yields, where present, are not necessarily the maximum attainable;

(vii) in general, the structures of end-products of the Formula I wereconfirmed by nuclear magnetic resonance (NMR) spectroscopy; NMR chemicalshift values were measured on the delta scale [proton magnetic resonancespectra were determined using a Bruker Avance 500 (500 MHz), BrukerAvance 400 (400 MHz), Bruker Avance 300 (300 MHz) or Bruker DRX (300MHz) instrument]; measurements were taken at ambient temperature unlessotherwise specified; the following abbreviations have been used: s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doubletof doublets; ddd, doublet of doublet of doublet; dt, doublet oftriplets; bs, broad signal.

(viii) in general, end-products of the Formula I were also characterizedby mass spectroscopy following liquid chromatography (LCMS or UPLC);UPLC was carried out using a Waters UPLC fitted with a Waters SQ massspectrometer (Column temp 40° C., UV=220-300 nm or 190-400 nm, MassSpec=ESI with positive/negative switching) at a flow rate of 1 mL/minusing a solvent system of 97% A+3% B to 3% A+97% B over 1.50 min (totalrun time with equilibration back to starting conditions, etc., 1.70min), where A=0.1% formic acid or 0.05% trifluoroacetic acid in water(for acidic work) or 0.1% ammonium hydroxide in water (for basic work)and B=acetonitrile. For acidic analysis the column used was a WatersAcquity HSS T3 (1.8 μm, 2.1×50 mm), for basic analysis the column usedwas a Waters Acquity BEH C18 (1.7 μm 2.1×50 mm). Alternatively, UPLC wascarried out using a Waters UPLC fitted with a Waters SQ massspectrometer (Column temp 30° C., UV=210-400 nm, Mass Spec=ESI withpositive/negative switching) at a flow rate of 1 mL/min using a solventgradient of 2 to 98% B over 1.5 mins (total run time with equilibrationback to starting conditions 2 min), where A=0.1% formic acid in waterand B=0.1% formic acid in acetonitrile (for acidic work) or A=0.1%ammonium hydroxide in water and B=acetonitrile (for basic work). Foracidic analysis the column used was a Waters Acquity HSS T3 (1.8 μm,2.1×30 mm), for basic analysis the column used was a Waters Acquity BEHC18 (1.7 μm, 2.1×30 mm); LCMS was carried out using a Waters Alliance HT(2795) fitted with a Waters ZQ ESCi mass spectrometer and a PhenomenexGemini-NX C18 (5 μm, 110 A, 2.1×50 mm column at a flow rate of 1.1mL/min 95% A to 95% B over 4 min with a 0.5 min hold where A=0.1% formicacid and B=0.1% formic acid in acetonitrile (for acidic work) or A=0.1%ammonium hydroxide in water and B=acetonitrile (for basic work).Additionally, LCMS was carried out using a Shimadzu UFLC fitted with aShimadzu LCMS-2020 mass spectrometer and a Waters HSS C18 (1.8 μm,2.1×50 mm) or Shim-pack XR-ODS (2.2 μm, 3.0×50 mm) or PhenomenexGemini-NX C18 (3 μm, 3.0×50 mm) column at a flow rate of 0.7 mL/min (forWaters HSS C18 column), 1.0 mL/min (for Shim-pack XR-ODS column) or 1.2mL/min (for Phenomenex Gemini-NX C18), 95% A to 95% B over 2.2 min witha 0.6 min hold, where A=0.1% formic acid or 0.05% trifluoroacetic acidin water (for acidic work) or 0.1% ammonium hydroxide or 6.5 mM ammoniumcarbonate in water (for basic work) and B=acetonitrile. The reportedmolecular ion corresponds to the [M+H]+ unless otherwise specified; formolecules with multiple isotopic patterns (Br, CI, etc.) the reportedvalue is the one obtained for the lowest isotope mass unless otherwisespecified.

(ix) ion exchange purification was generally performed using an SCX-2(Biotage) cartridge.

(x) intermediate purity was assessed by thin layer chromatographic, massspectroscopy, LCMS, UPLC/MS, HPLC (high performance liquidchromatography) and/or NMR analysis;

(xi) the following abbreviations have been used:—

-   -   ACN acetonitrile    -   BID twice a day    -   BSA bovine serum albumin    -   DCM dichloromethane    -   DMF N,N-dimethylformamide    -   DMSO dimethyl sulphoxide    -   dppf 1,1′-bis(diphenylphosphino)ferrocene    -   EA ethyl acetate    -   ee enantiomeric excess    -   equiv equivalents    -   e.r. enantiomeric ratio    -   EtOH ethanol    -   HATU        (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxid hexafluorophosphate)    -   HCl hydrochloric acid    -   HPMC hydroxypropyl methylcellulose    -   IPA Isopropanol    -   NaOH sodium hydroxide    -   NSCLC non-small cell lung cancer    -   QD four times a dat    -   TBME tert-butyl methyl ether    -   TEA triethylamine    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   Tos p-toluenesulfonyl    -   Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Intermediate 1: 1-[(4-Methylphenyl)sulfonyl]-7-nitro-1H-indole

A solution of NaOH (599 g, 14986.55 mmol) in water (1500 mL) was addedto a stirred mixture of 7-nitro-1H-indole (243 g, 1498.65 mmol) andtetrabutylammonium hydrogen sulfate (50.9 g, 149.87 mmol) in DCM (3000mL) at 25° C., over a period of 5 minutes under air. The resultingmixture was stirred at 25° C. for 20 minutes. 4-methylphenylsulfonylchloride (371 g, 1948.25 mmol) was added under air and the resultingmixture was stirred at 25° C. for 16 hours. The reaction mixture wasdiluted with DCM (2 L), and washed sequentially with water (500 mL×2),10% aqueous K₂CO₃ (500 mL×2), and 1 M HCl (500 mL×2) and saturated NaCl(500 mL×2). The organic layer was dried over Na₂SO₄, filtered andevaporated. When approximately 200 mL DCM was left, 500 mL EA was added.The solvent was removed under reduced pressure. When approximately 200mL EA was left, 1000 mL TBME was added. The precipitate was collected byfiltration, washed with TBME (1 L) and dried under vacuum to afford1-[(4-methylphenyl)sulfonyl]-7-nitro-1H-indole (402 g, 85%,Intermediate 1) as a white solid, which was used without furtherpurification; 1H NMR δ (DMSO-d6, 300 MHz) 2.39 (3H, s), 7.09 (1H, d),7.40-7.55 (3H, m), 7.75-7.85 (3H, m), 7.95-8.00 (1H, m), 8.06 (1H, d);m/z (ES+), [M+H]+=317.

Intermediate 2: 3-Bromo-1-[(4-methylphenyl)sulfonyl]-7-nitro-1H-indole

Bromine (81 mL, 1580 mmol) was added dropwise to1-[(4-methylphenyl)sulfonyl]-7-nitro-1H-indole (50 g, 158 mmol,Intermediate 1) in CCl₄ (1000 mL) at 80° C. The resulting solution wasstirred at 80° C. for 6 hours. The mixture was cooled to roomtemperature, concentrated and the residue was washed with ethyl acetateto afford 3-bromo-1-[(4-methylphenyl)sulfonyl]-7-nitro-1H-indole (53 g,85%, Intermediate 2) as a brown solid; ¹H NMR δ (DMSO-d6, 300 MHz) 2.41(3H, s), 7.55-7.62 (2H, m), 7.57 (1H, t), 7.85-7.92 (3H, m), 7.96 (1H,d), 8.49 (1H, s); m/z (ES−), [M−H]−=393.

Intermediate 3:1-[(4-Methylphenyl)sulfonyl]-7-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

A solution of 3-bromo-1-[(4-methylphenyl)sulfonyl]-7-nitro-1H-indole(200 g, 506 mmol, Intermediate 2),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (193 g, 759mmol), potassium acetate (99 g, 1012 mmol) and PdCl₂(dppf) (18.5 g, 25.3mmol) in 1,4-dioxane (1500 mL) was degassed with nitrogen three times,then the reaction mixture was stirred at 90° C. for 8 hours. The mixturewas cooled to room temperature and concentrated. The solids were treatedwith water and filtered. Washing with methanol and drying in vacuoafforded the1-[(4-methylphenyl)sulfonyl]-7-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(150 g, 67%, Intermediate 3) as a grey solid; ¹H NMR δ (Chloroform-d,400 MHz) 1.41 (12H, s), 2.47 (3H, s), 7.38-7.43 (3H, m), 7.66 (1H, d),7.87 (2H, d), 8.24 (1H, s), 8.29-8.32 (1H, d); m/z (ES+), [M+H]+=443.

Intermediate 4:3-(2-Chloro-4-pyrimidinyl)-1-[(4-methylphenyl)sulfonyl]-7-nitro-1H-indole

1-[(4-Methylphenyl)sulfonyl]-7-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(15 g, 33.9 mmol, Intermediate 3), 2,4-dichloropyrimidine (6.6 g, 44.1mmol), potassium carbonate (14.1 g, 101.7 mmol) and PdCl₂(dppf) (2.5 g,3.4 mmol) in dioxane (200 mL) and water (40 mL) were stirred undernitrogen at 80° C. for 12 hours. The solvent was removed under reducedpressure. The aqueous layer was extracted with THF (4×100 mL) andconcentrated to give3-(2-chloro-4-pyrimidinyl)-1-[(4-methylphenyl)sulfonyl]-7-nitro-1H-indole(12 g, 83%, Intermediate 4) as a brown solid, which was used withoutfurther purification; ¹H NMR δ (DMSO-d6, 300 MHz) 2.42 (3H, s), 7.52(2H, d), 7.68 (1H, t), 7.98 (3H, m), 8.31 (1H, d), 8.85-8.90 (2H, m),9.30 (1H, s); m/z (ES+), [M+H]+=429.

The procedure described above was repeated using the indicateddichloropyrimidine to give Intermediates 5-8 described in Table 2:

TABLE 2 m/z Yield Intermediate Dichloropyrimidine NMR δ (300 MHz) [M +H]+ % 5 3-(2-chloro-5-fluoro-4- pyrimidinyl)-1-[(4-methylphenyl)sulfonyl]- 7-nitro-1H-indole

DMSO-d6 2.43 (3H, s), 7.52 (2H, d), 7.70 (1H, t), 8.00 (3H, m), 8.76(1H, s), 8.82 (1H, d), 9.04 (1H, d) 447 76 6 3-(2-chloro-5-methyl-4-pyrimidinyl)-1-[(4- methylphenyl)sulfonyl]- 7-nitro-1H-indole

DMSO-d6 2.47 (3H, s), 2.50 (3H, s), 7.56 (2H, d), 7.68 (1H, dd), 7.97(2H, d), 8.04 (1H, d), 8.47 (1H, d), 8.68 (1H, s), 8.85 (1H, s) 443 83 73-(2,5-dichloro-4- pyrimidinyl)-1-[(4- methylphenyl)sulfonyl]-7-nitro-1H-indole

DMSO-d6 2.40 (3H, s), 7.52 (2H, d), 7.65 (1H, d), 7.91 (2H, d), 8.00(1H, d), 8.50 (1H, d), 8.88 (1H, s), 9.06 (1H, s) 463 82 83-(5-bromo-2-chloro-4- pyrimidinyl)-1-[(4- methylphenyl)sulfonyl]-7-nitro-1H-indole

DMSO-d6 2.38 (3H, s), 7.46 (2H, d), 7.62 (1H, t), 7.88 (2H, d), 7.95(1H, d), 8.35 (1H, d), 8.88 (1H, s), 9.16 (1H, s) 509 51

Intermediate 9: 3-(2-Chloro-4-pyrimidinyl)-7-nitro-1H-indole

3-(2-Chloro-4-pyrimidinyl)-1-[(4-methylphenyl)sulfonyl]-7-nitro-1H-indole(1 g, 2.3 mmol, Intermediate 4) and sodium hydroxide (1.86 g, 46.6 mmol)in THF (10 mL) and water (5 mL) was stirred at 50° C. for 2 hours. Thesolvent was removed under reduced pressure. The crude product waspurified by flash silica chromatography, elution gradient 0 to 10%methanol in ethyl acetate. Pure fractions were evaporated to dryness toafford 3-(2-chloro-4-pyrimidinyl)-7-nitro-1H-indole (0.52 g, 81%,Intermediate 9) as a yellow solid; ¹H NMR δ (DMSO-d6, 300 MHz) 7.45 (1H,t), 8.10 (1H, s), 8.19 (1H, d), 8.60 (1H, d), 8.66 (1H, s), 8.94 (1H,d), 12.70 (1H, s); m/z (ES+), [M+H]+=275.

The procedure described above was repeated using the indicated StartingIntermediate to give Intermediates 10-13 described in Table 3:

TABLE 3 Starting m/z Intermediate Intermediate NMR δ (300 MHz) [M + H]+Yield % 10 5 DMSO-d6 7.42 (1H, t), 8.14 293 89 3-(2-chloro-5-fluoro-4-(1H, d), 8.33 (1H, d), 8.69 pyrimidinyl)-7-nitro-1H- (1H, d), 8.92 (1H,d) 12.72 indole (1H, s) 11 6 DMSO-d6 2.52 (3H, s), 7.46 289 773-(2-chloro-5-methyl-4- (1H, t), 8.20 (1H, s), 8.24pyrimidinyl)-7-nitro-1H- (1H, d), 8.62 (1H, s), 8.89 indole (1H, d),12.65 (1H, s) 12 7 DMSO-d6 7.50 (1H, t), 8.24 309 70 3-(2,5-dichloro-4-(1H, d), 8.65 (1H, m), 8.89 pyrimidinyl)-7-nitro-1H- (1H, s), 8.92 (1H,d), 12.78 indole (1H, s) 13 8 DMSO-d6 7.48 (1H, t), 8.25 355 803-(5-bromo-2-chloro-4- (1H, d), 8.75 (1H, s), 8.83pyrimidinyl)-7-nitro-1H- (1H, d), 8.97 (1H, d), 12.77 indole (1H, s)

Intermediate 14:N-(3-Methoxy-1-methyl-1H-pyrazol-4-yl)-4-(7-nitro-1H-indol-3-yl)pyrimidin-2-amine

3-(2-Chloro-4-pyrimidinyl)-7-nitro-1H-indole (300 mg, 1.1 mmol,Intermediate 9), 3-methoxy-1-methyl-1H-pyrazol-4-amine dihydrochloride(328 mg, 1.64 mmol) and 4-methylbenzenesulfonic acid monohydrate (623mg, 3.28 mmol) were dissolved in isopropanol (16 mL) and sealed into amicrowave tube. The reaction was heated at 130° C. for 2 hours in themicrowave reactor and cooled to room temperature. The reaction wasconcentrated under reduced pressure and then filtered to giveN-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-4-(7-nitro-1H-indol-3-yl)pyrimidin-2-amine(300 mg, 75%, Intermediate 14) as a yellow solid and was used in thenext step directly without further purification; ¹H NMR δ (DMSO-d6, 300MHz) 3.77 (3H, s), 3.83 (3H, s), 7.39-7.49 (1H, m), 7.70 (1H, d), 7.83(1H, s), 825-8.43 (2H, m), 8.71 (1H, d), 9.33 (1H, br s), 10.26 (1H, brs), 12.91 (1H, s); m/z (ES+), [M+H]+=366.

The procedure described above was repeated using the indicatedaminopyrazole and Starting Intermediate to give Intermediates 15-22described in Table 4:

TABLE 4 Starting m/z Yield Intermediate Intermediate Aminopyrazole NMR δ(300 MHz) [M + H]+ % 15 5-fluoro-N- (3-methoxy-1- methyl-1H-pyrazol-4-yl)-4-(7-nitro-1H- 10

DMSO-d6 3.71 (3H, s), 3.78 (3H, s), 7.32 (1H, t), 7.68 (1H, s), 8.13(1H, d), 8.17-8.27 (1H, m), 8.37 (1H, d), 8.55 (1H, s), 12.52 (1H, s)384 84 indol-3-yl) pyimidin-2-amine 16 N-(3-methoxy- 1-methyl-1H-pyrazol-4-yl)-5- methyl-4-(7-nitro- 11

DMSO-d6 2.36 (3H, s), 3.68 (3H, s), 3.80 (3H, s7.26 (1H, t), 7.65 (1H,s), 8.01 (1H, s), 8.15-8.23 (2H, m)), 8.93 (1H, br s), 12.35 (1H, br s)380 95 1H-indol-3-yl)- 2-pyrimidinamine 17 5-chloro-N-(3-methoxy-1-methyl- 1H-pyrazol-4-yl)-4- (7-nitro-1H-indol-3- 12

Not obtained 400 55 yl)pyrimidin-2-amine 18 5-bromo-N-(3-methoxy-1-methyl- 1H-pyrazol-4-yl)- 4-(7-nitro-1H-indol- 13

Not obtained 444 80 3-yl)pyrimidin- 2-amine 19 N-(3-ethoxy-1-methyl-1H-pyrazol- 4-yl)-5-fluoro-4- (7-nitro-1H-indol-3- 10

DMSO-d6 1.25 (3H, t), 3.73 (3H, s), 4.18 (2H, q), 7.20-7.53 (1H, m),7.68 (1H, s), 8.11-8.30 (2H, m), 8.35 (1H, d), 8.43 (1H, s), 9.04 (1H,s) 398 74 yl)pyrimidin-2-amine 20 N-(3-ethoxy-1- methyl-1H-pyrazol-4-yl)-5-methyl-4- (7-nitro-1H-indol-3- 11

DMSO-d6 1.25 (3H, t), 2.36 (3H, s), 3.68 (3H, s), 4.16 (2H, q), 7.27(1H, t), 7.64 (1H, s), 7.95-8.15 (2H, m), 8.20 (2H, m), 8.94 (1H, br s),12.35 (1H, s) 394 74 yl)pyrimidin-3-amine 21 N-(1,3-dimethyl-1H-pyrazol-4-yl)-5- methyl-4-(7-nitro- 1H-indol-3-yl) 11

DMSO-d6 2.09 (3H, s), 2.47 (3H, s), 3.81 (3H, s), 7.38 (1H, s), 7.87(1H, s), 8.19-8.33 (3H, m), 9.66 (1H, s), 12.79 (1H, s) 364 62pyrimidin-2-amine 22 5-chloro-N-(3- ethoxy-1-methyl- 1H-pyrazol-4-yl)-4-(7-nitro-1H- 12

Not obtained 414 100 indol-3-yl)pyrimidin- 2-amine

Intermediate 23:3-{2-[(3-Methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-amine

Iron (0.46 g, 8.2 mmol) was added toN-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-4-(7-nitro-1H-indol-3-yl)pyrimidin-2-amine(0.6 g, 1.6 mmol, Intermediate 14) and ammonium chloride (0.88 g, 16.4mmol) in THF (100 mL) and water (50 mL) at 25° C. under nitrogen. Theresulting mixture was stirred at 80° C. for 2 hours. The reactionmixture was filtered through diatomaceous earth. The solvent was removedunder reduced pressure and the crude product was purified by flash C18silica chromatography, elution gradient 30 to 80% methanol in water.Pure fractions were evaporated to dryness to afford3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-amine(0.41 g, 74%, Intermediate 23) as a yellow solid; ¹H NMR δ (DMSO-d6, 400MHz) 3.68 (3H, s), 3.72 (3H, s), 5.10 (2H, s), 6.40 (1H, d), 6.82 (1H,t), 7.05 (1H, d), 7.60-7.73 (2H, m), 8.05 (1H, s), 8.10-8.21 (2H, m),11.29 (1H, s); m/z (ES+), [M+H]+=336.

The procedure described above was repeated using the indicated StartingIntermediate to give Intermediates 24-31 described in Table 5:

TABLE 5 Starting m/z Intermediate Intermediate NMR δ (300 MHz) [M + H]+Yield % 24 15 DMSO-d6 3.71 (3H, s), 354 79 3-{5-fluoro-2-[(3-methoxy-1-3.79 (3H, s), 5.17 (2H, s), methyl-1H-pyrazol-4- 6.44 (1H, d), 6.83 (1H,t), yl)amino]pyrimidin-4-yl}-1H- 7.67 (1H, s), 7.79 (1H, s),indol-7-amine 8.04-8.10 (1H, m), 8.19- 8.26 (2H, m), 11.48 (1H, s) 25 16DMSO-d6 2.32 (3H, s), 350 61 3-{2-[(3-methoxy-1-methyl- 3.66 (3H, s),3.79 (3H, s), 1H-pyrazol-4-yl)amino]-5- 5.10 (2H, br s), 6.40 (1H,methylpyrimidin-4-yl}-1H- dd), 6.79 (1H, t), 7.68 (2H, indol-7-amine s),7.81-7.92 (2H, m), 8.11 (1H, s), 11.23 (1H, s) 26 17 DMSO-d6 3.77 (3H,s), 370 67 3-{5-chloro-2-[(3-methoxy-1- 3.81 (3H, s), 5.12 (2H, s),methyl-1H-pyrazol-4- 6.40 (1H, d), 6.79 (1H, d),yl)amino]pyrimidin-4-yl}-1H- 6.88 (1H, s), 7.55-7.60 indol-7-amine (1H,m), 8.26 (1H, s), 8.35 (2H, s), 11.41 (1H, s) 27 18 DMSO-d6 3.63 (3H,s), 414 92 3-{5-bromo-2-[(3-methoxy-1- 3.78 (3H, s), 5.12 (2H, s),methyl-1H-pyrazol-4- 6.40 (1H, d), 6.90 (1H, t),yl)amino]pyrimidin-4-yl}-1H- 7.60-7.65 (2H, m), 8.37 indol-7-amine (2H,s), 8.43 (1H, d), 11.37 (1H, s) 28 21 Not 334 70 3-{2-[(1,3-dimethyl-1H-obtained pyrazol-4-yl)amino]-5- methylpyrimidin-4-yl}-1H- indol-7-amine29 19 DMSO-d6 1.25 (3H, t), 368 67 3-{2-[(3-ethoxy-1-methyl-1H- 3.68(3H, s), 4.14 (2H, q), pyrazol-4-yl)amino]-5- 5.15 (2H, s), 6.43 (1H,d), fluoropyrimidin-4-yl}-1H- 6.82 (1H, t), 7.64 (1H, s), indol-7-amine7.78 (1H, s), 8.01-8.17 (2H, m), 8.22 (1H, d), 11.46 (1H, s) 30 20Methanol-d4 1.38 (3H, t), 364 93 3-{2-[(3-ethoxy-1-methyl-1H- 2.39 (3H,s), 3.72 (3H, s), pyrazol-4-yl)amino]-5- 4.26 (2H, q), 6.64 (1H, d),methylpyrimidin-4-yl}-1H- 6.96 (1H, t), 7.74 (3H, m), indol-7-amine 8.14(1H, s) - four exchangeable protons not observed 31 22 Not 384 563-{5-chloro-2-[(3-ethoxy-1- obtained methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H- indol-7-amine

Intermediate 32:(2S)-2-Bromo-N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)propanamide

1-Propanephosphonic acid cyclic anhydride (25.6 g, 40.3 mmol) was addeddropwise to3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-amine(4.5 g, 13.4 mmol, Intermediate 23), (S)-2-bromopropanoic acid (4.1 g,26.8 mmol) and pyridine (3.3 mL, 40.3 mmol) in ethyl acetate (100 mL) at−50° C. over a period of 30 minutes under nitrogen. The resultingmixture was stirred at −50° C. for 1 hour. The reaction was allowed towarm up to −15° C. and stirred for 16 hour. The reaction mixture wasquenched with ice water (100 mL), extracted with ethyl acetate (3×200mL), the organic layer was dried, filtered and evaporated to afford atan solid. The crude product was purified by flash silicachromatography, elution gradient 100 to 0% petroleum ether in ethylacetate. Pure fractions were evaporated to dryness to afford(2S)-2-bromo-N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)propanamide(4.9 g, 78%, Intermediate 32) as a yellow solid; ¹H NMR δ (DMSO-d6, 400MHz) 1.76 (3H, d), 3.60 (1H, m), 3.62 (3H, s), 3.71 (3H, s), 4.83 (1H,q), 7.01-7.16 (2H, m), 7.41 (1H, d), 7.71 (1H, s), 8.20 (1H, d), 8.26(1H, d), 8.27 (1H, s), 10.12 (1H, s), 11.26 (1H, s); m/z (ES+),[M+H]+=470.

The procedure described above was repeated using the indicated StartingIntermediate to give Intermediates 33-36 described in Table 6:

TABLE 6 Starting m/z Intermediate Intermediate NMR δ (300 MHz) [M + H]+Yield % 33 24 DMSO-d6 1.85 (3H, d), 3.72 490 94(2S)-2-bromo-N-(3-{5-fluoro- (3H, s), 3.79 (3H, s), 4.812-[(3-methoxy-1-methyl-1H- (1H, q), 7.09 (1H, t), 7.50pyrazol-4-yl)amino]pyrimidin- (1H, d), 7.67 (1H, s), 8.194-yl}-1H-indol-7- (1H, t), 8.29 (1H, d), 8.39 yl)propanamide (2H, d),10.22 (1H, s), 11.43 (1H, s) 34 25 DMSO-d6 1.84 (3H, d), 2.33 484 66(2S)-2-bromo-N-(3-{2-[(3- (3H, s), 3.68 (3H, s), 3.78methoxy-1-methyl-1H- (3H, s), 4.80 (1H, q), 7.03 pyrazol-4-yl)amino]-5-(1H, t), 7.45 (1H, d), 7.66 methylpyrimidin-4-yl}-1H- (1H, s), 7.99 (1H,s), 8.00 indol-7-yl)propanamide (1H, s), 8.15 (1H, s), 8.26 (1H, s),10.14 (1H, s), 11.22 (1H, s) 35 29 DMSO-d6 1.24 (3H, t), 1.84 502 86(2S)-2-bromo-N-(3-{2-[(3- (3H, d), 3.70 (3H, s), 4.14ethoxy-1-methyl-1H-pyrazol- (2H, q), 4.80 (1H, q), 7.074-yl)amino]-5-fluoropyrimidin- (1H, t), 7.49 (1H, d), 7.654-yl}-1H-indol-7- (1H, s), 8.18 (1H, t), 8.28 yl)propanamide (3H, d),10.21 (1H, s), 11.27- 11.63 (1H, m) 36 30 DMSO-d6 1.30 (3H, t), 1.86 500(Br 62 (2S)-2-bromo-N-(3-{2-[(3- (3H, d), 2.35 (3H, s), 3.60- isotopeethoxy-1-methyl-1H-pyrazol- 3.65 (1H, m), 3.68 (3H, s), value)4-yl)amino]-5- 4.11 (2H, q), 4.84 (1H, q), methylpyrimidin-4-yl}-1H-7.03 (1H, t), 7.47 (1H, d), indol-7-yl)propanamide 7.66 (1H, s), 7.95(1H, s), 8.17 (1H, s), 8.28 (1H, s), 10.15 (1H, s), 11.23 (1H, s)

Intermediate 37: (R)-2-(4-Methylpiperazin-1-yl)propanoic aciddihydrochloride

Trifluoromethanesulfonic anhydride (53.6 mL, 317 mmol) was addeddropwise to (S)-methyl 2-hydroxypropanoate (30 g, 288 mmol) and2,6-lutidine (37 mL, 317 mmol) in DCM (500 mL) at −78° C. over a periodof 1 hour. The resulting solution was stirred at −78° C. for 0.5 hours.

The solution was then warmed to room temperature for 1 hour. The organicphase was washed with 1N HCl (aq.) (2×100 mL) and dried over sodiumsulfate, then filtered and evaporated. The residue was dissolved in DCM(500 mL), cooled to 0° C., then 1-methylpiperazine (65 g, 646 mmol) wasadded slowly. Potassium carbonate (212 g, 1537 mmol) in water (700 mL)was added dropwise at 0° C. The solution was stirred at 25° C.overnight, then washed with brine, dried over sodium sulfate, filteredand evaporated to give a yellow oil. 6N (aq.) HCl (270 mL, 1625 mmol)was added in one portion at 25° C. and the resulting mixture was stirredat 110° C. for 18 hours. The solution was evaporated and the productwashed with acetonitrile (200 mL) to afford an off-white solid. Thissolid was suspended in isopropanol (1000 mL) and was stirred for 3 hoursat 100° C. and then stirred for 16 hours at room temperature. Theprecipitate was collected by filtration, washed with isopropanol (150mL) and dried under vacuum to afford(2R)-2-(4-methylpiperazin-1-yl)propanoic acid dihydrochloride (15 g,48%, Intermediate 37) as a white solid; ¹H NMR δ (D20, 400 MHz) 1.51(3H, d), 2.94 (3H, s), 3.48-4.13 (9H, m); m/z (ES+), [M+H]+=173.

The procedure described above was repeated using the indicated2-hydroxypropanoate and piperazine to give the Intermediates 38 and 39described in Table 7:

TABLE 7 Hydroxy- m/z Yield Intermediate Piperazine propanoate NMR δ (300MHz) [M + H]+ % 38 (2S)-2-(4- methylpiperazin-1- yl)propanoic aciddihydrochloride

(R)-methyl-2- hydroxypropanoate DMSO-d6 1.54 (3H, d), 2.83 (3H, s), 3.69(8H, d), 4.30 (1H, s), 11.84 (1H, s) 173 100 39 (2R)-2-[(2R)-2,4-dimethylpiperazin- 1-yl]propanoic acid dihydrochloride

(S)-methyl-2- hydroxypropanoate Methanol-d4 1.26 (3H, d), 1.43 (3H, d),2.90 (4H, s), 3.05-3.21 (2H, m), 3.34-3.40 (2H, m), 3.42-3.49 (1H, m),3.53 (1H, br s), 4.07 (1H, q) 187 95

Intermediate 40:3-(2-Chloro-5-methyl-4-pyrimidinyl)-7-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indole

Sodium hydride (60% dispersion in mineral oil) (1.3 g, 33 mmol) wasadded portion-wise to a stirred suspension of3-(2-chloro-5-methyl-4-pyrimidinyl)-7-nitro-1H-indole (6.4 g, 22 mmol,Intermediate 11) in anhydrous THF (150 mL) at 0° C. After stirring for25 minutes, (2-(chloromethoxy)ethyl)trimethylsilane (4.1 mL, 23 mmol)was added rapidly dropwise. After 5 minutes the cooling bath was removedand the reaction left to stir at ambient temperature for 1.5 hours.Additional sodium hydride (60% dispersion in mineral oil) (130 mg, 3.3mmol) and (2-(chloromethoxy)ethyl)trimethylsilane (0.4 mL, 2.3 mmol)were added. The reaction was stirred for an additional 40 minutes thenquenched with saturated aqueous NaHCO₃ and the pale yellow mixture wasdiluted with ether. The layers were separated and the aqueous layerextracted with ether. The combined organic layer was washed with brine,dried over magnesium sulfate, filtered and evaporated. The residue wasdissolved in chloroform and was subject to silica gel chromatographyusing 5-45% ethyl acetate-hexane as eluent to afford3-(2-chloro-5-methyl-4-pyrimidinyl)-7-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indole(9.2 g, 100%, Intermediate 40) as a yellow solid; ¹H NMR δ (DMSO-d6, 400MHz) −0.16 (9H, s), 0.60-0.73 (2H, m), 2.51-2.52 (3H, m), 3.11-3.22 (2H,m), 5.72 (2H, s), 7.48 (1H, t), 7.94 (1H, dd), 8.57 (1H, s), 8.64 (1H,s), 8.84 (1H, dd); m/z (ES+), [M+H]+=419.

Intermediate 41:N-(3-Methoxy-1-methyl-1H-pyrazol-4-yl)-5-methyl-4-(7-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indol-3-yl)pyrimidin-2-amine

A mixture of dioxane and water (10:1, 44 mL) was added to a mixture of3-(2-chloro-5-methyl-4-pyrimidinyl)-7-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indole(1.59 g, 3.8 mmol, Intermediate 40),3-methoxy-1-methyl-1H-pyrazol-4-amine dihydrochloride (1.7 g, 10.4mmol), palladium(II) acetate (0.085 g, 0.4 mmol), Xantphos (0.22 g, 0.4mmol) and cesium carbonate (4.95 g, 15.2 mmol) under nitrogen. Themixture was then heated at 110° C. for 3.5 hours under nitrogen. Themixture was allowed to cool to ambient temperature, diluted with ethylacetate, filtered through diatomaceous earth and concentrated. Theresultant gum was subject to silica gel chromatography using 30-100%ethyl acetate-hexane as eluent to affordN-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-5-methyl-4-(7-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indol-3-yl)pyrimidin-2-amine(1.3 g, 67%, Intermediate 41) as a pale yellow solid; ¹H NMR δ (DMSO-d6,400 MHz) −0.17 (9H, s), 0.60-0.74 (2H, m), 2.35 (3H, s), 3.05-3.20 (2H,m), 3.68 (3H, s), 3.79 (3H, s), 5.69 (2H, s), 7.23-7.36 (1H, m), 7.65(1H, s), 7.86 (1H, d), 8.19 (1H, br s), 8.23 (1H, s), 8.35 (1H, s),8.67-9.02 (1H, m); m/z (ES+), [M+H]+=510.

Intermediate 42:3-{2-[(3-Methoxy-1-methyl-1H-pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indol-7-amine

A mixture ofN-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-5-methyl-4-(7-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indol-3-yl)pyrimidin-2-amine(1.26 g, 2.5 mmol, Intermediate 41) in methanol-ethyl acetate (1:1, 20mL) was subject to hydrogenation at atmospheric pressure in the presenceof 10% palladium on carbon (w/w) (0.26 g, 0.25 mmol) at ambienttemperature for 23 hours. The slurry was diluted with ethyl acetate andfiltered through diatomaceous earth, then concentrated to afford3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indol-7-amine(1.1 g, 93%, Intermediate 42) as a pale yellow solid; ¹H NMR δ (DMSO-d6,400 MHz) −0.05 (9H, s), 0.86-0.96 (2H, m), 2.30 (3H, s), 3.51-3.62 (2H,m), 3.65 (3H, s), 3.79 (3H, s), 4.97-5.05 (2H, m), 5.72 (2H, s), 6.53(1H, d), 6.83 (1H, t), 7.65 (1H, s), 7.70 (1H, br s), 7.90 (1H, s), 7.95(1H, s), 8.13 (1H, s); m/z (ES+), [M+H]+=480.

Intermediate 43: 2-(4-Methylpiperazin-1-yl)butanoic acid

Ethyl 2-bromobutanoate (30 g, 154 mmol) was added dropwise to1-methylpiperazine (61.6 g, 615 mmol) in THF (500 mL) at 0° C. over aperiod of 30 minutes under nitrogen. The resulting mixture was stirredat 25° C. for 12 hours. The solvent was removed under reduced pressure.The mixture was made basic with saturated aqueous potassium carbonateand extracted with ethyl acetate (3×150 mL). The combined organic layerswere evaporated to give a yellow oil which was added dropwise to 6N(aq.) HCl (200 mL, 1200 mmol) at 0° C. over a period of 10 minutes underair. The resulting mixture was stirred at 100° C. for 16 hours. Thereaction mixture was cooled to room temperature before being washed withethyl acetate (100 mL). The water was removed under reduced pressure togive 2-(4-methylpiperazin-1-yl)butanoic acid hydrochloride (35 g, 96%,Intermediate 43) as a white solid that was used in the next stepdirectly without further purification; ¹H NMR δ (DMSO-d6, 300 MHz) 0.93(3H, t), 1.76-2.09 (2H, m), 2.80 (3H, s), 3.29-3.69 (8H, m), 3.99 (1H,br s), 11.84 (1H, s); m/z (ES+), [M+H]+=187.

Intermediate 44: Methyl 3-methoxy-2-(4-methylpiperazin-1-yl)propanoate

Potassium carbonate (1.38 g, 10.1 mmol) was added to a stirred solutionof 1-methylpiperazine (0.93 mL, 8.3 mmol) and methyl2-bromo-3-methoxypropanoate (1.7 g, 8.6 mmol) in acetonitrile (20 mL)under a nitrogen atmosphere. The pale yellow mixture was then warmed to60° C. for 21 hours. The reaction was cooled to ambient temperature,diluted with ethyl acetate and filtered. Concentration afforded methyl3-methoxy-2-(4-methylpiperazin-1-yl)propanoate (1.69 g, 94%) as anorange oil which was used without further purification; ¹H NMR δ(DMSO-d6, 400 MHz) 2.12 (3H, s), 2.20-2.36 (4H, m), 2.48-2.56 (5H, m),3.21-3.25 (3H, s), 3.39 (1H, dd), 3.48-3.53 (1H, m), 3.63 (3H, s); m/z(ES+), [M+H]+=217.

Intermediate 45: Lithium 3-methoxy-2-(4-methylpiperazin-1-yl)propanoate

A solution of lithium hydroxide (52 mg, 2.2 mmol) in water (3 mL) wasadded to a stirred solution of methyl3-methoxy-2-(4-methylpiperazin-1-yl)propanoate (0.47 g, 2.2 mmol,Intermediate 44) in THF (3 mL) at ambient temperature. After stirringfor 21 hours the reaction was warmed to 40° C. for 22 hours. A few dropsof methanol were added, clarifying the pale yellow solution and heatingcontinued. After 2 hours, additional lithium hydroxide (16 mg, 0.7 mmol)was added and the reaction left to stir for 4 days. The solvent wasremoved under reduced pressure and the aqueous solution lyophilized toafford the lithium 3-methoxy-2-(4-methylpiperazin-1-yl)propanoate (0.45g, 98%) as an off-white solid; ¹H NMR δ (DMSO-d6, 400 MHz) 2.10 (3H, s),2.27 (4H, br s), 2.51-2.60 (4H, m), 2.87 (1H, t), 3.19 (3H, s),3.50-3.60 (2H, m); m/z (ES+), [M+H]+=203.

The procedure described for Example 32 was repeated using the indicatedStarting Intermediates to give Intermediates 46 and 47 described inTable 8:

TABLE 8 Starting m/z Intermediate Intermediates NMR δ (400 MHz) [M + H]+Yield % 46 42 and 43 DMSO-d6 −0.07 (9H, s), 0.86 648 81N-(3-{2-[(3-methoxy-1- (2H, dd), 0.98 (3H, t), 1.68-methyl-1H-pyrazol-4- 1.84 (2H, m), 2.33 (4H, s), yl)amino]-5- 2.80 (2H,br s), 3.07 (3H, m), methylpyrimidin-4-yl}-1-{2- 3.17 (4H, s), 3.40-3.52(4H, [2- m), 3.67 (3H, s), 3.79 (3H, (trimethylsilyl)ethoxy]ethyl}- s),5.66-5.75 (2H, m), 7.10 1H-indol-7-yl)-2-(4- (1H, t), 7.34 (1H, d), 7.65methylpiperazin-1- (1H, s), 8.05 (1H, br s), 8.11 yl)butanamide (1H, s),8.18 (1H, s), 9.33 (1H, br s), 9.72 (1H, s) 47 42 and 45 DMSO-d6 −0.08(9H, s), 0.83- 664 82 3-methoxy-N-(3-{2-[(3- 0.94 (2H, m), 2.33 (3H, s),methoxy-1-methyl-1H- 2.58-3.14 (11H, m), 3.41- pyrazol-4-yl)amino]-5-3.51 (3H, m), 3.67 (3H, s), methylpyrimidin-4-yl}-1-{[2- 3.70-3.86 (6H,m), 5.64- (trimethylsilyl)ethoxy]meth- 5.86 (3H, m), 7.09 (1H, t),yl}-1H-indol-7-yl)-2-(4- 7.30 (1H, d), 7.64 (1H, s), methylpiperazin-1-8.05 (1H, s), 8.10 (1H, s), yl)propanamide 8.18 (1H, s), 8.30 (1H, brs), 9.36 (1H, br s), 9.84 (1H, s)

Intermediate 48: 3-(2-Chloropyrimidin-4-yl)-1H-indol-7-amine

Ammonium chloride (7.8 g, 146 mmol) was added to3-(2-chloro-4-pyrimidinyl)-7-nitro-1H-indole (4 g, 14.6 mmol,Intermediate 9) and iron (4.1 g, 72 mmol) in THF (200 mL) and water (100mL) at 25° C. under nitrogen. The resulting mixture was stirred at 80°C. for 12 hours. The reaction mixture was filtered through diatomaceousearth. The organic phase was separated and the aqueous phase wasextracted with THF (2×100 mL). The organic phases were combined andconcentrated to afford 3-(2-chloropyrimidin-4-yl)-1H-indol-7-amine (3 g,84%, Intermediate 48) as a green solid; ¹H NMR δ (DMSO-d6, 400 MHz) 5.42(2H, s), 6.44 (1H, d), 6.91 (1H, m), 7.60 (1H, d), 7.78-7.91 (1H, m),8.36 (1H, s), 8.45 (1H, d)-NH proton obscured; m/z (ES+), [M+MeCN]+=286.

The procedure described above for Intermediate 48 was repeated using theindicated Starting Intermediate to give Intermediates 49 and 50described in Table 9:

TABLE 9 Starting m/z Intermediate Intermediate NMR δ (400 MHz) [M + H]+Yield % 49 11 DMSO-d6 2.50 (3H, s), 5.26 (2H, s), 259 80 3-(2-chloro-5-6.47 (1H, dd), 6.92 (1H, t), 7.76 (1H, methylpyrimidin-4- d), 8.12 (1H,d), 8.45 (1H, s), 11.71 yl)-1H-indol-7-amine (1H, d) 50 10 Methanol-d46.68 (1H, dd), 7.06 263 79 3-(2-chloro-5- (1H, t), 8.04 (1H, dd), 8.18(1H, d), fluoropyrimidin-4-yl)- 8.39 (1H, d) - three exchangeable1H-indol-7-amine protons not observed

Intermediate 51:N-[3-(2-Chloropyrimidin-4-yl)-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)butanamide

1-Propanephosphonic acid cyclic anhydride (7.8 g, 12.3 mmol) was addeddropwise to 3-(2-chloropyrimidin-4-yl)-1H-indol-7-amine (1 g, 4.1 mmol,Intermediate 48), 2-(4-methylpiperazin-1-yl)butanoic aciddihydrochloride (1.3 g, 4.9 mmol, Intermediate 43) and pyridine (2 mL,25 mmol) in DMF (100 mL) at 0° C. over a period of 10 minutes undernitrogen. The resulting mixture was stirred at 25° C. for 2 hours. Thesolvent was removed under reduced pressure and the crude productpurified by reverse phase silica (C18) gel chromatography using 0-100%methanol in water to giveN-[3-(2-chloropyrimidin-4-yl)-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)butanamide(0.24 g, 14%, Intermediate 51) as a yellow solid; ¹H NMR δ (Methanol-d4,300 MHz) 1.08 (3H, t), 1.79-2.02 (2H, m), 2.32 (3H, s), 2.58 (4H, s),2.84 (4H, m), 3.10-3.27 (1H, m), 7.25 (2H, m), 7.77 (1H, d), 8.27 (1H,s), 8.37 (1H, dd), 8.44 (1H, d)-two exchangeable protons not observed;m/z (ES+), [M+H]+=413.

The procedure described above for Intermediate 51 was repeated using theindicated Starting Intermediates to give Intermediates 52-55 describedin Table 10:

TABLE 10 Starting m/z Intermediate Intermediates NMR δ (300 MHz) [M +H]+ Yield % 52 50 and 43 Not 431 89 N-[3-(2-chloro-5- obtainedfluoropyrimidin-4-yl)- 1H-indol-7-yl]-2-(4- methylpiperazin-1-yl)butanamide 53 50 and 45 DMSO-d6 2.27 (3H, s), 447 47N-[3-(2-chloro-5- 2.41 (4H, br s), 2.64 (2H, fluoropyrimidin-4-yl)- m),2.77 (2H, m), 3.29 1H-indol-7-yl]-3- (3H, s), 3.50-3.73 (2H,methoxy-2-(4- m), 3.79 (1H, dd), 7.23 methylpiperazin-1- (1H, t), 7.59(1H, dd), yl)propanamide 8.29-8.44 (2H, m), 8.71 (1H, d), 9.97 (1H, s),11.85 (1H, s) 54^(1,2) 49 and 37 DMSO-d6 1.28 (3H, d), 413 81(R)-N-[3-(2-chloro-5- 2.24 (3H, s), 2.51-2.71 methylpyrimidin-4-yl)-(11H, m), 3.39 (1H, m), 1H-indol-7-yl]-2-(4- 7.18 (1H, t), 7.50 (1H, d),methylpiperazin-1- 8.19 (1H, s), 8.31 (1H, d), yl)propanamide 8.52 (1H,s), 9.76 (1H, s), 11.69 (1H, s) 55³ 50 and 37 DMSO-d6 1.27 (3H, d), 41779 (R)-N-[3-(2-chloro-5- 2.27 (3H, s), 2.35-2.68 fluoropyrimidin-4-yl)-(8H, m), 3.39 (1H, q), 1H-indol-7-yl]-2-(4- 7.24 (1H, t), 7.53 (1H, d),methylpiperazin-1- 8.34-8.37 (2H, m), 8.72 yl)propanamide (1H, d), 9.83(1H, s), 11.90 (1H, s) ¹1H NMR analysis was performed using a BrukerAvance 400 (400 MHz) spectrometer. ²The indicated amino acid (1.5 equiv)and 7-amino-indole intermediates were reacted in the presence of HATU (2equiv) and diisopropylethylamine (4 equiv) in DMF at room temperature.³The indicated amino acid (1.3 equiv) and 7-amino-indole intermediateswere reacted in the presence of HATU (1.5 equiv) anddiisopropylethylamine (5 equiv) in DMF at room temperature.

Intermediate 56:3-(2-Chloropyrimidin-4-yl)-7-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indole

3-(2-Chloropyrimidin-4-yl)-7-nitro-1H-indole (4.4 g, 16 mmol,Intermediate 9) was dissolved in THF (60 mL) and cooled to 0° C. Sodiumhydride (1.2 g, 29 mmol) was then added and the reaction mixture waswarmed to room temperature. (2-(Chloromethoxy)ethyl)trimethylsilane (4.3mL, 24 mmol) was then slowly added and the reaction mixture was allowedto stir for 1.5 hours. The reaction mixture was quenched with aqueoussodium bicarbonate, and extracted with ethyl acetate. The organic layerswere dried over sodium sulfate, filtered, and concentrated giving thecrude product as a red oil which was purified via silica gel columnchromatography using 0-40% ethyl acetate-hexanes as eluent to give3-(2-chloropyrimidin-4-yl)-7-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indole(5.7 g, 88%, Intermediate 56) as a yellow solid; ¹H NMR δ (DMSO-d6, 300MHz) −0.16 (9H, s), 0.67 (2H, t), 3.19 (2H, t), 5.66 (2H, s), 7.51 (1H,s), 7.88-8.01 (2H, m), 8.71 (1H, d), 8.88 (1H, s), 8.91 (1H, s); m/z(ES+), [M+H]+=405.

Intermediate 57:3-(2-Chloropyrimidin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indol-7-amine

3-(2-Chloropyrimidin-4-yl)-7-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indole(5.7 g, 14.1 mmol, Intermediate 56) was dissolved in methanol (47 mL),THF (47 mL) and water (47 mL).

The solution was then heated to 60° C. and ammonium chloride (32.8 g,612 mmol) was added, followed by iron (34.4 g, 617 mmol). The solutionwas then allowed to stir for 2 hours at 60° C. The reaction mixture waspartitioned between water and diethyl ether. The organic layers wereextracted and combined, dried over sodium sulfate, filtered, andconcentrated to give3-(2-chloropyrimidin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indol-7-amine(5.2 g, 98%, Intermediate 57) as a yellow oil; ¹H NMR δ (DMSO-d6, 300MHz) −0.04 (9H, m), 0.92 (2H, t), 3.60 (2H, t), 5.15 (2H, s), 5.71 (2H,s), 6.59-6.62 (1H, m), 7.00 (1H, t), 7.70 (1H, dd), 7.80 (1H, d), 8.50(1H, s), 8.55 (1H, d); m/z (ES+), [M+H]+=375.

Intermediate 58:(2R)—N-[3-(2-Chloropyrimidin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propanamide

(R)-2-(4-Methylpiperazin-1-yl)propanoic acid dihydrochloride (2.45 g, 10mmol, Intermediate 37) was dissolved in DMF (15 mL) anddi(1H-imidazol-1-yl)methanone (1.3 g, 8 mmol) was added. Gas evolved,and the reaction mixture was allowed to stir under nitrogen at roomtemperature until the reaction mixture became homogeneous.3-(2-Chloropyrimidin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indol-7-amine(1.5 g, 4 mmol, Intermediate 57) in DMSO (11 mL) was then added and thereaction mixture was stirred overnight. The reaction was quenched with10% potassium carbonate solution and extracted with ethyl acetate. Theorganic layers were combined, dried over sodium sulfate, filtered, andconcentrated. The crude product was purified via silica gel columnchromatography using 100% ethyl acetate then 0-20% methanol-DCM aseluent to give(2R)—N-[3-(2-chloropyrimidin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propanamide(0.92 g, 43%, Intermediate 58) as a yellow solid; ¹H NMR δ(Chloroform-d, 300 MHz) −0.10 (9H, s), 0.96-1.08 (2H, m), 1.40 (3H, d),2.36 (3H, m), 2.47-2.92 (8H, m), 3.27 (1H, q), 3.51-3.64 (2H, m),5.54-5.79 (2H, m), 7.36 (1H, t), 7.58 (1H, d), 7.79 (1H, d), 7.96 (1H,s), 8.12 (1H, d), 8.54 (1H, d), 9.72 (1H, br s); m/z (ES+), [M+H]+=529.

Intermediate 59:(2R)—N-[3-(2-Chloropyrimidin-4-yl)-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propanamide

(2R)—N-[3-(2-Chloropyrimidin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propanamide(0.38 g, 0.7 mmol, Intermediate 58) was dissolved in DMSO (7 mL) andcesium fluoride (0.32 g, 2.1 mmol) was added. The reaction mixture wasthen heated at 100° C. and allowed to stir for 2 hours. The reactionmixture was diluted with ethyl acetate and water. The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate. Theorganic layers were combined, dried over sodium sulfate, filtered, andconcentrated to give(2R)—N-[3-(2-chloropyrimidin-4-yl)-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propanamide(0.17 g, 59%) as a yellow solid; ¹H NMR δ (Chloroform-d, 300 MHz) 1.43(3H, d), 2.32-3.02 (11H, m), 3.39 (1H, m), 6.84 (1H, m), 7.22-7.25 (1H,m), 7.52 (1H, d), 8.03 (1H, d), 8.34 (1H, d), 8.47 (1H, d), 9.81 (1H,br. s), 11.58 (1H, br s); m/z (ES+), [M+H]+=399.

Example 1:(2R)-2-[(2S)-2,4-Dimethylpiperazin-1-yl]-N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-H-indol-7-yl)propanamide

(S)-1,3-Dimethylpiperazine dihydrochloride (0.16 g, 0.85 mmol) was addedin one portion to(2S)-2-bromo-N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)propanamide(0.2 g, 0.43 mmol, Intermediate 32) and potassium carbonate (0.24 g, 1.7mmol) in DMF (2 mL) at 0° C. The resulting solution was stirred at 25°C. for 16 hours. The crude product was purified by preparative HPLC (XBridge C18, 5 μm, 19×150 mm; Mobile Phase A: water/0.05% TFA, MobilePhase B: acetonitrile; Flow rate: 20 mL/min; Gradient: 20% B to 70% B in10 min; 254 nm) to afford(2R)-2-[(2S)-2,4-dimethylpiperazin-1-yl]-N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)propanamide(49 mg, 23%, Example 1) as a white solid; 1H NMR δ (Methanol-d4, 400MHz) 1.15 (3H, d), 1.43 (3H, d), 2.06 (1H, t), 2.32 (3H, s), 2.41 (1H,m), 2.75-2.92 (3H, m), 3.01 (2H, m), 3.79-3.83 (4H, m), 3.94 (3H, s),7.12-7.19 (3H, dt), 7.73 (1H, s), 8.09 (1H, s), 8.19 (1H, d), 8.27 (1H,s); m/z (ES+), [M+H]+=504; chiral HPLC (ChiralPak ADH, 5 μm, 0.46×10 cm,mobile phase: 1:1 hexanes (modified with 0.1% TEA) and ethanol at 1.0mL/min) indicates 99:1 e.r., retention time=9.24 min.

The procedure described above for Example 1 was repeated using theindicated piperazine and Starting Intermediate to give the compoundsdescribed in Table 11:

TABLE 11 Starting m/z Yield Example Intermediate Piperazine NMR δ (300MHz) [M + H]+ %  2 33

Methanol-d4 1.14 (3H, d), 1.42 (3H, d), 2.26-2.38 (5H, m), 2.52 (2H, m),2.86- 3.01 (3H, m), 3.39 (1H, m), 3.79 (3H, s), 3.92 (3H, s), 7.10-7.22(2H, m), 7.68 (1H, s), 8.14 (2H, dd), 8.42 (1H, s) 522 47  3¹ 33

Methanol-d4 1.42 (3H, d), 2.61-2.84 (10H, m), 3.36 (4H, s), 3.58 (2H,t), 3.79 (3H, s), 3.91 (3H, s), 7.10- 7.22 (2H, m), 7.68 (1H, s), 8.14(2H, dd), 8.42 (1H, s) 552 70  4¹ 33

Methanol-d4 1.15 (3H, t), 1.43 (3H, d), 2.51 (2H, q), 2.56-2.90 (8H, m),3.34- 3.45 (1H, m), 3.79 (3H, s), 3.92 (3H, s), 7.10-7.22 (2H, m), 7.68(1H, s), 8.14 (2H, dd), 8.42 (1H, s) 522 62  5 33

Methanol-d4 1.14 (3H, d), 1.42 (3H, dd), 2.18 (1H, t), 2.36 (4H, s),2.50 (1H, m), 2.61-2.72 (1H, m), 2.86- 3.00 (3H, m), 3.33-3.44 (1H, m),3.79 (3H, s), 3.92 (3H, s), 7.10-7.22 (2H, m), 7.68 (1H, s), 8.14 (2H,dd), 8.42 (1H, s) 522 60  6 33

Methanol-d4 1.23 (3H, d), 1.30 (3H, d), 2.20 (1H, m), 2.35 (3H, s), 2.42(1H, m), 2.68 (1H, m), 2.79 (1H, m), 2.85 (3H, m), 3.80 (3H, s), 3.92(3H, s), 4.06 (1H, m), 7.07-7.20 (2H, m), 7.68 (1H, s), 8.14 (2H, dd),8.43 (1H, s) 522 22  7a² 33

Methanol-d4 1.17 (3H, d), 1.45 (3H, d), 2.10 (1H, t), 2.33 (3H, s), 2.41(1H, s), 2.72-2.96 (3H, m), 3.02 (2H, m), 3.73-3.87 (4H, m), 3.92 (3H,s), 7.16 (2H, d), 7.69 (1H, s), 8.15 (2H, dd), 8.43 (1H, s) 522 35  7b²33

Methanol-d4 1.23 (3H, d), 1.31 (3H, d), 2.17 (1H, m), 2.34 (4H, m),2.60-2.94 (5H, m), 3.80 (3H, s), 3.92 (3H, s), 4.07 (1H, d), 7.13 (2H,m), 7.69 (1H, s), 8.15 (2H, dd), 8.44 (1H, s) 522 15  8¹ 35

Methanol-d4 1.13 (3H, t), 1.32 (3H, t), 1.42 (3H, d), 2.49 (2H, d),2.55-2.94 (8H, m), 3.40 (1H, m), 3.77 (3H, s), 4.23 (2H, q), 7.08- 7.21(2H, m), 7.66 (1H, s), 8.13 (2H, dd), 8.41 (1H, d) 536 62  9¹ 35

Methanol-d4 1.32 (3H, t), 1.41 (3H, d), 2.52-2.95 (10H, m), 3.33-3.44(4H, m), 3.56 (2H, t), 3.77 (3H, s), 4.23 (2H, q), 7.04-7.26 (2H, m),7.66 (1H, s), 8.12 (2H, dd), 8.41 (1H, m) 566 57 10a³ 35

Methanol-d4 1.19 (3H, d), 1.34 (3H, t), 1.46 (3H, d), 2.25 (1H, t), 2.44(3H, s), 2.58 (1H, m), 2.85-3.02 (3H, m), 3.03-3.13 (2H, m), 3.80 (3H,s), 3.82-3.90 (1H, m), 4.25 (2H, q), 7.09- 7.20 (2H, m), 7.69 (1H, s),8.15 (2H, dd), 8.43 (1H, s) 536 51 10b³ 35

Methanol-d4 1.19-1.40 (9H, m), 2.17 (1H, t), 2.34 (4H, s), 2.60-2.91(5H, m), 3.79 (3H, s), 4.06 (1H, m), 4.25 (2H, q), 7.06-7.22 (2H, m),7.69 (1H, s), 8.14 (2H, dd), 8.44 (1H, d) 536 12 11a⁴ 35

Methanol-d4 1.13 (3H, d), 1.32 (3H, t), 1.41 (3H, d), 2.16 (1H, t), 2.33(4H, s), 2.47 (1H, td), 2.65 (1H, td), 2.81-2.99 (3H, m), 3.32- 3.43(1H, m), 3.77 (3H, s), 4.23 (2H, q), 7.07-7.22 (2H, m), 7.67 (1H, s),8.13 (2H, dd), 8.41 (1H, d) 536 84 11b⁴ 35

Methanol-d4 1.11 (3H, d), 1.32 (3H, t), 1.40 (3H, d), 2.22-2.37 (5H, m),2.42- 2.59 (2H, m), 2.84-3.02 (3H, m), 3.31-3.44 (1H, m), 3.77 (3H, s),4.23 (2H, q), 7.07-7.22 (2H, m), 7.67 (1H, s), 8.13 (2H, dd), 8.41 (1H,s) 536 12 12 35

Methanol-d4 1.21 (3H, d), 1.26-1.38 (6H, m), 2.16 (1H, t), 2.33 (4H, s),2.57- 2.95 (5H, m), 3.77 (3H, s), 4.04 (1H, q), 4.23 (2H, q), 6.91-7.22(2H, m), 7.67 (1H, s), 8.12 (2H, dd), 8.42 (1H, d) 536 33 13 35

Methanol-d4 1.11 (3H, d), 1.32 (3H, t), 1.40 (3H, d), 2.22-2.40 (5H, m),2.42- 2.59 (2H, m), 2.90 (3H, dd), 3.35-3.42 (1H, m), 3.77 (3H, s), 4.23(2H, q), 7.06- 7.21 (2H, m), 7.67 (1H, s), 8.13 (2H, dd), 8.42 (1H, brs) 536 88 14⁵ 34

Methanol-d4 1.13 (3H, d), 1.41 (3H, d), 2.16 (1H, t), 2.36 (6H, d),2.54-2.41 (1H, m), 2.66 (1H, t), 2.91 (3H, q), 3.72 (3H, s), 3.92 (3H,s), 7.21-7.04 (2H, m), 7.70 (1H, s), 7.87 (1H, s), 8.14 (1H, s), 8.20(1H, d) 518 19 15 34

DMSO-d6 1.26 (3H, d), 2.33 (3H, s), 2.35-2.78 (10H, m), 3.33-3.35 (1H,m), 3.42- 3.65 (2H, m), 3.67 (3H, s), 3.79 (3H, s), 4.36 (1H, s), 7.00(1H, t), 7.41 (1H, d), 7.66 (1H, s), 7.95 (1H, s), 7.97 (1H, s), 8.14(1H, s), 8.16 (1H, br s), 9.65 (1H, s), 11.28 (1H, s) 534 39 16 34

Chloroform-d 1.17 (3H, t), 1.40 (3H, d), 2.35 (3H, s), 2.39-3.02 (10H,m), 3.37 (1H, d), 3.70 (3H, s), 3.98 (3H, s), 6.52 (1H, s), 6.81 (1H,d), 7.12 (1H, t), 7.66 (1H, d), 7.82 (1H, s), 8.14- 8.30 (2H, m), 9.78(1H, s), 11.17 (1H, s) 518 75 17 34

Methanol-d4 1.40 (3H, d), 2.35 (3H, s), 2.75 (10H, m), 3.37 (4H, s),3.57 (2H, t), 3.70 (3H, s), 3.98 (3H, s), 6.54 (1H, s), 6.81 (1H, d),7.12 (1H, t), 7.66 (1H, d), 7.81 (1H, s), 8.17-8.32 (2H, m), 9.80 (1H,s), 11.7 (1H, s) 548 78 18 34

Methanol-d4 1.25 (3H, s), 1.39 (3H, d), 2.35 (3H, s), 2.48 (4H, d), 2.62(3H, s), 2.94 (3H, d), 3.45 (1H, s), 3.70 (3H, s), 3.98 (3H, s), 6.53(1H, s), 6.82-7.19 (2H, m), 7.64 (1H, d), 7.81 (1H, s), 8.13-8.37 (2H,m), 9.68 (1H, s), 11.19 (1H, s) 518 22 19 34

Methanol-d4 1.11 (3H, d), 1.39 (3H, d), 1.95-2.11 (1H, m), 2.31 (7H, d),2.61- 2.89 (3H, m), 2.92-3.07 (2H, m), 3.68 (4H, s), 3.88 (3H, s),6.98-7.17 (2H, m), 7.66 (1H, s), 7.82 (1H, s), 8.09 (2H, s) 518 6 20 36

DMSO-d6 0.98 (3H, t), 1.20- 1.31 (6H, m), 2.31-2.78 (13H, m), 3.31 (1H,s), 3.65 (3H, s), 4.15 (2H, q), 7.00 (1H, t), 7.41 (1H, d), 7.64 (1H,s), 7.86-7.98 (2H, m), 8.14 (1H, s), 8.22 (1H, s), 9.66 (1H, s), 11.30(1H, s) 532 44 21 36

DMSO-d6 1.20-1.31 (6H, m), 2.33 (3H, s), 2.45-2.70 (10 H, m), 3.21 (3H,s), 3.26- 3.30 (1H, m), 3.41 (2H, t), 3.65 (3H, s), 4.15 (2H, q), 7.00(1H, t), 7.41 (1H, d), 7.64 (1H, s), 7.86-7.99 (2H, m), 8.14 (1H, s),8.22 (1H, s), 9.65 (1H, s), 11.29 (1H, s) 562 62 22 36

Chloroform-d 1.13 (3H, d), 1.44-1.62 (6H, m), 2.13- 2.24 (1H, m),2.25-2.63 (6H, m), 2.64-2.68 (2H, m), 2.71-2.83 (1H, m), 2.84- 2.98 (3H,m), 3.53 (1H, s), 3.72 (3H, s), 4.32 (2H, q), 6.63 (1H, s), 6.83 (1H,s), 7.17 (1H, t), 7.34 (1H, s), 7.68 (1H, d), 7.87 (1H, s), 8.25 (2H,t), 11.18 (1H, s) 532 28 23 36

Methanol-d4 1.20-1.43 (9H, m), 2.19 (1H, t), 2.38 (7H, d), 2.66-2.90(5H, m), 3.73 (3H, s), 4.02-4.14 (1H, m), 4.26 (2H, q), 7.12 (2H, d),7.73 (1H, s), 7.88 (1H, s), 8.13-8.27 (2H, m) 532 12 24 36

Methanol-d4 1.14 (3H, d), 1.29-1.47 (6H, m), 2.28- 2.45 (8H, m), 2.52(2H, t), 2.86-3.04 (3H, m), 3.40 (1H, d), 3.73 (3H, d), 4.26 (2H, q),7.15 (2H, dt), 7.73 (1H, d), 7.89 (1H, s), 8.13- 8.27 (2H, m) 532 46 2533

Methanol-d4 1.42 (3H, d), 2.34 (3H, s), 2.48-2.89 (8H, m), 3.40 (1H, m),3.79 (3H, s), 3.91 (3H, s), 7.10 7.22 (2H, m), 7.68 (1H, s), 8.14 (2H,dd), 8.42 (1H, br s) 508 72 26 32

Methanol-d4 1.14 (3H, d), 1.41 (3H, d), 2.15-2.18 (1H, m), 2.36 (4H, m),2.50- 2.53 (1H, m), 2.64-2.71 (1H, m), 2.88-2.94 (3H, m), 3.40 (1H, m),3.79 (3H, s), 3.94 (3H, s), 7.12-7.17 (3H, m), 7.73 (1H, s), 8.09 (1H,s), 8.19 (1H, d), 8.29 (1H, br s) 504 56 27¹ 32

Methanol-d4 1.38 (3H, d), 2.59-2.78 (10H, m), 3.33 (3H, s), 3.38 (1H,m), 3.52 (2H, m), 3.75 (3H, s), 3.90 (3H, s), 7.09-7.13 (3H, m), 7.69(1H, s), 8.05 (1H, s), 8.15 (1H, d), 8.25 (1H, br s) 534 45 28 32

Methanol-d4 1.08 (3H, t), 1.38 (3H, d), 2.43-2.51 (1H, q), 2.61-2.77(8H, m), 3.37 (1H, m), 3.75 (3H, s), 3.90 (3H, s), 7.08-7.13 (3H, m),7.68 (1H, s), 8.04 (1H, s), 8.14 (1H, d), 8.24 (1H, br s) 504 54 29 32

Methanol-d4 1.14 (3H, d), 1.19 (3H, d), 2.08-2.15 (1H, m), 2.29-2.41(4H, m), 2.60-2.83 (5H, m), 3.75 (3H, s), 3.90 (3H, s), 4.02 (1H, m),7.08-7.14 (3H, m), 7.68 (1H, s), 8.04 (1H, s), 8.14 (1H, d), 8.24 (1H,d) 504 43 30⁶ 32

Methanol-d4 1.12 (3H, d), 1.40 (3H, d), 2.27-2.48 (5H, m), 2.51-2.57(2H, m), 2.88-2.99 (3H, m), 3.40 (2H, m), 3.79 (3H, s), 3.94 (3H, s),7.12-7.17 (3H, m), 7.73 (1H, s), 8.09 (1H, s), 8.19 (1H, d), 8.29 (1H,s)- two exchangeable protons not observed 504 42 31a⁷ 36

Methanol-d4 1.15 (3H, d), 1.31-1.48 (6H, m), 2.16- 2.24 (1H, m), 2.38(6H, d)), 2.52-2.56 (1H, m), 2.65- 2.69 (1H, m), 2.29-2.99 (3H, m), 3.33(2H, m), 3.73 (3H, s), 4.86 (2H, q), 7.17 (2H, m), ), 7.73 (1H, s), 7.89(1H, s), 8.16 (1H, s), 8.21 (1H, d)-)-two exchangeable protons notobserved 532 22 31b⁷ 36

Methanol-d4 1.14 (d, 3H), 1.30-1.50 (m, 6H), 2.25-2.38 (m, 4H), 2.41 (s,3H), 2.45- 2.60 (m, 2H), 2.85-3.10 (m, 3H), 3.35-3.46 (m, 2H), 3.73 (s,3H), 4.25 (q, 2H), 7.05- 7.25 (m, 2H), 7.73 (s, 1H), 7.89 (s, 1H), 8.16(s, 1H), 8.25 (d, 1H) 532 33 ¹The appropriate piperazine and2-bromo-acetamide intermediate were combined in DMF according to theprocedure of Example 1. Potassim carbonate was not used. ²The indicatedpiperazine and 2-bromo-acetamide intermediate were reacted under theconditions described by the procedure for Example 1. Chiral purificationon a preparative chiral-HPLC using a Lux Cellulose-4 column (isocraticelution with 50% EtOH in isohexane modified with 0.2% IPA) to affordExample 7a (isolated as the second eluting peak, retention time = 9.45min) and Example 7b (isolated as the first eluting peak, retention time= 7.54 min). Stereochemical assignment of the enantiomers was made basedon the major product formation of the reaction and validated bybiological activity against JAK1 in the Enzyme Inhibition Studies, asshown in Example 66. ³The indicated piperazine and 2-bromo-acetamideintermediate were reacted under the conditions described by theprocedure for Example 1. The crude product was purified by preparativechiral-HPLC on a Lux Cellulose-4 column, isocratic with 25% EtOH inisohexane (modified with 0.2% IPA) as eluent to afford Example 10a(first eluting peak, retention time = 5.02 min) and Example 10b, (secondeluting peak, retention time = 6.68 min). Stereochemical assignment ofthe enantiomers was made based on the major product formation of thereaction and validated by biological activity against JAK1 in the EnzymeInhibition Studies, as shown in Example 66. ⁴The indicated piperazineand 2-bromo-acetamide intermediate were reacted under the conditionsdescribed by the procedure for Example 1. The crude product was purifiedby preparative chiral-HPLC (ADH column, isocratic with 50% EtOH inisohexane (modified with 0.2% IPA) as eluent) to give Example 11a (firsteluting peak, retention time = 3.61 min) and Example 11b (second elutingpeak, retention time = 4.60 min). Stereochemical assignment of theenantiomers was made based on the major product formation of thereaction and validated by biological activity against JAK1 in the EnzymeInhibition Studies, as shown in Example 66. ⁵The appropriate piperazine(2 equiv) and racemic 2-bromo-acetamide intermediate (1 equiv) werecombined in 1,4-dioxane in the presence of silver oxide (4 equiv).Chiral-HPLC separation (ChiralPak IA column, isocratic with 50% EtOH inn-hexane (modified with 0.1% diethylamine) as eluent) was performed toafford Example 14 (retention time = 3.99 min). Stereochemical assignmentof the enantiomers was made based on the biological activity againstJAK1 in the Enzyme Inhibition Studies, as shown in Example 66. ⁶The e.r.was determined to be 94:6 by chiral-HPLC analysis (ChiralPak IA-3, 3 μm,0.46 × 5 cm, mobile phase: 50% ethanol in hexanes (modified with 0.2%IPA) at 1.0 mL/min), retention time = 2.99 min. ⁷The indicatedpiperazine and racemic 2-bromo-acetamide intermediate were reacted inthe presence of silver oxide (8.0 equivalents) in 1,4-dioxane at roomtemperature for 2 hours. The crude product was purified by preparativechiral-HPLC (Chiralpak IB column, isocratic with 50% Hexanes in EtOH(modified with 0.1% TEA) as eluent) to afford Example 31a (analyticalchiral-HPLC: Chiralpak IA, 5 μ silica, 0.46 × 25 cm column, hexanes(0.1% TEA):EtOH (60:40) at 1.0 mL/min as the eluent, retention time =8.18 min) isolated as the first eluting peak and Example 31b (analyticalchiral-HPLC: Chiralpak IA, 5 μ silica, 0.46 × 25 cm column, hexanes(0.1% TEA):EtOH (60:40) at 1.0 mL/min as the eluent, retention time =9.55 min) isolated as the second eluting peak. Stereochemical assignmentof the enantiomers was made based on the biological activity againstJAK1 in the Enzyme Inhibition Studies, as shown in Example 66.

Example 32:(2R)—N-(3-{2-[(3-Methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide

3-{2-[(3-Methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-amine(180 mg, 0.54 mmol, Intermediate 23),(R)-2-(4-methylpiperazin-1-yl)propanoic acid dihydrochloride (158 mg,0.64 mmol, Intermediate 37) and HATU (408 mg, 1.1 mmol) in THF (5 mL)were stirred together to give an orange solution. Diisopropylethylamine(0.38 mL, 2.2 mmol) was added at 25° C. The resulting suspension wasstirred at 25° C. for 3 hours. The reaction mixture was diluted withethyl acetate (100 mL), and washed with saturated aqueous Na₂CO₃ (50mL), water (50 mL) and brine (50 mL). The organic layer was dried,filtered and evaporated to afford crude product. The crude product waspurified by preparative HPLC (XSelect CSH Prep C18 OBD column, 5 μm,19×150 mm), employing a gradient of 30-70% acetonitrile in 0.03% aqueousammonia as eluents. Fractions containing the desired compound wereevaporated to dryness to afford(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide(125 mg, 48%, Example 32) as a white solid; ¹H NMR δ (DMSO, 400 MHz)1.26 (3H, d), 2.16 (3H, s), 2.25-2.45 (4H, m), 2.51-2.70 (4H, m), 3.71(3H, s), 3.80 (3H, s), 7.05 (1H, t), 7.13 (1H, d), 7.38 (1H, d), 7.70(1H, s), 8.16-8.31 (4H, m), 9.62 (1H, s), 11.35 (1H, s)—the α-proton tothe amide is masked by the residual water peak; m/z (ES+), [M+H]+=490.

The procedure described above for Example 32 was repeated using theindicated Intermediates to give Examples 33-42 described in Table 12:

TABLE 12 Starting m/z Example Intermediates NMR δ (400 MHz) [M + H]+Yield % 33 25 and 38 DMSO-d6 with D2O 1.28 (3H, d), 2.27 504 13 (3H, s),2.73 (3H, s), 2.85-3.34 (8H, m), 3.44 (1H, q), 3.63 (3H, s), 374 (3H,s), 7.04 (1H, t), 7.19 (1H, d), 7.55 (1H, s), 7.91 (1H, s), 8.08 (2H,s), 8.26 (1H, s) -two exchangeable protons not observed 34 25 and 37DMSO-d6 1.26 (3H, d), 2.16 (3H, s), 504 72 2.33 (3H, s), 2.38 (4H, s),2.57-2.62 (4H, m), 3.33 (1H, q), 3.67 (3H, s), 3.79 (3H, s), 7.00 (1H,t), 7.41 (1H, d), 7.66 (1H, s), 7.96 (2H, t), 8.14 (1H, s), 8.22 (1H,s), 9.65 (1H, s), 11.28 (1H, s) 35 30 and 37 Methanol-d4 1.34 (3H, t),1.40 (3H, d), 518 16 2.32 (3H, s), 2.37 (3H, s), 2.50-2.80 (8H, m), 3.38(1H, q), 3.69 (3H, s), 4.34 (2H, q), 7.05-7.20 (2H, m), 7.69 (1H, s),7.85 (1H, s), 8.23 (1H, s), 8.17 (1H, d)-three exchangeable protons notobserved 36 26 and 37 DMSO-d6 1.26 (3H, d), 2.27 (3H, s), 524 482.24-2.52 (4H, m), 2.53-2.70 (4H, m), 3.30-3.36 (1H, m), 3.69 (3H, s),3.78 (3H, s), 7.02 (1H, s), 7.40 (1H, d), 7.65 (1H, s), 8.32 (1H, s),8.48 (1H, s), 9.69 (1H, s), 11.42 (1H, s) 37 27 and 37 DMSO-d6 1.26 (3H,d), 2.17 (3H, s), 568 49 2.23-2.45 (4H, m), 2.46-2.71 (4H, m), 3.30-3.32(1H, m), 3.68 (3H, s), 3.78 (3H, s), 7.01 (1H, s), 7.37 (1H, d), 7.64(1H, s), 8.42 (1H, s), 8.45-8.56 (2H, m), 9.70 (1H, s), 11.36 (1H, s) 3825 and 39 Chloroform-d 1.19 (3H, d), 1.35 (3H, d), 518 19 2.10 (1H, m),2.26 (1H, m), 2.38 (6H, m), 2.69 (2H, t), 2.89 (3H, m), 3.72 (3H, s),3.91 (1H, q), 4.00 (3H, s), 6.57 (1H, s), 6.80 (1H, d), 7.15 (1H, t),7.68 (1H, d), 7.84 (1H, s), 8.06-8.36 (2H, m), 9.88 (1H, s), 11.15 (1H,s) 39 29 and 37 Methanol-d4 1.34 (3H, t), 1.43 (3H, d), 522 25 2.35 (3H,s), 2.50-2.85 (8H, m), 3.41 (1H, q), 3.79 (3H, s), 4.24 (2H, q), 7.10-7.22 (2H, m), 7.68 (1H, s), 8.13 (1H, d), 8.16 (1H, d), 8.43 (1H,s)-three exchangeable protons not observed 40 31 and 37 Methanol-d4 1.33(3H, t), 1.42 (3H, d), 538 22 2.35 (3H, s), 2.63-2.71 (4H, m), 2.77-2.81 (4H, m), 3.42 (1H, q), 3.76 (3H, s), 4.26 (2H, q), 7.10-7.20 (2H,m), 7.70 (1H, s), 8.28 (2H, m), 8.48 (1H, m)-three exchangeable protonsnot observed 41 28 and 37 Chloroform-d 1.41 (3H, d), 2.29 (3H, s), 48836 2.36 (3H, s), 2.42 (3H, s), 2.67-2.80 (8H, m), 3.38 (1H, q), 3.80(3H, s), 6.42 (1H, s), 6.82 (1H, d), 7.12 (1H, t), 7.69 (1H, d), 7.88(1H, s), 8.21 (2H, m), 9.74 (1H, s), 11.18 (1H, s) 42 28 and 38 DMSO-d61.27 (3H, d), 2.12 (3H, s), 488 4 2.17 (3H, s), 2.35 (3H, s), 2.40 (4H,s), 2.57-2.63 (4H, m), 3.72 (3H, s), 7.03 (1H, t), 7.43 (1H, d), 7.81(1H, s), 7.97 (1H, d), 8.19 (2H, m), 8.37 (1H, s), 9.68 (1H, s), 11.33(1H, s)

Examples 43 and 44:(2S)—N-(3-{2-[(3-Methoxy-1-methyl-1H-pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)butanamideand(2R)—N-(3-{2-[(3-Methoxy-1-methyl-1H-pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)butanamide

Cesium fluoride (143 mg, 0.94 mmol) was added to a stirring solution ofN-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}-1-{2-[2-(trimethylsilyl)ethoxy]ethyl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)butanamide(203 mg, 0.31 mmol, Intermediate 46) in anhydrous DMSO (3 mL). Themixture was heated at 80° C. under nitrogen for 4 hours then allowed tocool to ambient temperature. The reaction was diluted with ethyl acetatethen water and the phases separated. The aqueous phase was extractedwith ethyl acetate then the combined organic phase was washed withbrine, dried over magnesium sulfate, and concentrated. The resultantresidue was subject to silica gel chromatography using 5-20%methanol-DCM as eluent to afford a pale tan solid (101 mg). Chiralseparation was performed by chiral-HPLC: Chiralpak ID, 4.6×50 mm, 3, 50%hexane 50% 1:1 methanol-ethanol (modified with 0.1% diethylamine) togive(2S)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)butanamide(17 mg, 11%, Example 43); Chiral HPLC: >99:1 e.r., retention time=2.34min; ¹H NMR δ (Dichloromethane-d2, 400 MHz) 1.09 (3H, t), 1.84-1.93 (2H,m), 2.29 (3H, s), 2.36 (3H, s), 2.51 (4H, br s), 2.67 (2H, br s), 2.75(2H, m), 3.03 (1H, t), 3.67 (3H, s), 3.93 (3H, s), 6.49 (1H, s), 6.82(1H, d), 7.12 (1H, t), 7.72 (1H, d), 7.79 (1H, s), 8.20 (1H, s), 8.24(1H, d), 9.62 (1H, s), 11.06 (1H, br s); m/z (ES+) [M+H]+=518; followedby(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-5-methylpyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)butanamide(18 mg, 11%, Example 44); Chiral HPLC: −99:5 e.r., retention time=2.78min; ¹H NMR δ (Dichloromethane-d2, 400 MHz) 1.09 (3H, t), 1.84-1.93 (2H,m), 2.29 (3H, s), 2.36 (3H, s), 2.51 (4H, br s), 2.67 (2H, br s), 2.75(2H, m), 3.03 (1H, t), 3.67 (3H, s), 3.93 (3H, s), 6.49 (1H, s), 6.82(1H, d), 7.12 (1H, t), 7.72 (1H, d), 7.79 (1H, s), 8.20 (1H, s), 8.24(1H, d), 9.62 (1H, s), 11.06 (1H, br s); m/z (ES+), [M+H]+=518.Stereochemical assignment of the enantiomers was made based on thebiological activity against JAK1 in the Enzyme Inhibition Studies, asshown in Example 66.

The procedure described above for Examples 43 and 44 was repeated usingthe indicated Starting Intermediates to give Examples 45 and 46described in Table 13:

TABLE 13 Starting m/z Example Intermediate NMR δ (400 MHz) [M + H]+Yield % 45¹ 47 Methanol-d4 2.31 (3H, s), 2.37 (3H, s), 534 26 2.58 (4H,br s), 2.81 (2H, br s), 2.86- 2.99 (2H, m), 3.41 (3H, s), 3.49 (1H, t),3.70 (3H, s), 3.79-3.87 (1H, m), 3.88- 3.96 (4H, m), 7.06-7.12 (1H, m),7.13- 7.18 (1H, m), 7.69 (1H, s), 7.86 (1H, s), 8.12 (1H, s), 8.19 (1H,d)-three exchangeable protons not observed 46¹ 47 Methanol-d4 2.31 (3H,s), 2.37 (3H, s), 534 28 2.58 (4H, br s), 2.81 (2H, br s), 2.86- 2.99(2H, m), 3.41 (3H, s), 3.49 (1H, t), 3.70 (3H, s), 3.79-3.87 (1H, m),3.88- 3.96 (4H, m), 7.06-7.12 (1H, m), 7.13- 7.18 (1H, m), 7.69 (1H, s),7.86 (1H, s), 8.12 (1H, s), 8.19 (1H, d)-three exchangeable protons notobserved ¹Chiral separation was performed by preparative chiral-SFC(Chiralcel OD, 5 μm, 4.6 × 100 mm) with 35% MeOH (modified with 0.1%dimethylethylamine) as eluent at 5 mL/min at 40° C., to afford Example46 (first eluting peak, retention time = 2.54 min) and Example 45(second eluting peak, retention time = 3.10 min). Stereochemicalassignment of the enantiomers was made based on the biological activityagainst JAK1 in the Enzyme Inhibition Studies, as shown in Example 66.

Examples 47 and 48:(2R)—N-(3-{2-[(3-Methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)butanamideand(2S)—N-(3-{2-[(3-Methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)butanamide

N-[3-(2-Chloropyrimidin-4-yl)-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)butanamide(0.22 g, 0.53 mmol, Intermediate 51),3-methoxy-1-methyl-1H-pyrazol-4-amine dihydrochloride (0.16 g, 0.8 mmol)and 4-methylbenzenesulfonic acid monohydrate (0.2 g, 1.1 mmol) weredissolved in isopropanol (6 mL) and sealed into a microwave tube. Thereaction was heated at 120° C. for 2 hours in the microwave reactor andcooled to room temperature. The crude product was purified bypreparative HPLC (XBridge Prep C18 OBD column, 5μ silica, 19×150 mm),using decreasingly polar mixtures of water (containing 0.2% formic acid)and acetonitrile as eluents. Fractions containing the desired compoundwere evaporated to dryness to afford racemicN-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)butanamide(90 mg, 34%) as a white solid; m/z (ES+), [M+H]+=504. The product waspurified by preparative chiral-HPLC on an IC-3 column, isocratica with30% ethanol in isohexane (modified with 0.2% isopropanol) as eluent. Thefractions containing the desired compound were evaporated to dryness toafford firstly(2S)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)butanamide(32 mg, 35%, Example 48) as a white solid; ¹H NMR δ (Methanol-d4, 300MHz) 1.08 (3H, t), 1.89 (2H, dt), 2.33 (3H, s), 2.59 (4H, br s), 2.83(4H, br s), 3.21 (1H, dd), 3.80 (3H, s), 3.94 (3H, s), 7.10-7.27 (3H,m), 7.74 (1H, s), 8.11 (1H, s), 8.21 (1H, d), 8.30 (1H, s)—threeexchangeable protons not observed; m/z (ES+), [M+H]+=504; chiral HPLC:100% ee, retention time=4.48 min; followed by(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)butanamide(32 mg, 35%, Example 47) as a white solid; ¹H NMR δ (Methanol-d4, 300MHz) 1.08 (3H, t), 1.89 (2H, dt), 2.33 (3H, s), 2.59 (4H, br s), 2.83(4H, br s), 3.21 (1H, dd), 3.80 (3H, s), 3.94 (3H, s), 7.10-7.27 (3H,m), 7.74 (1H, s), 8.11 (1H, s), 8.21 (1H, d), 8.30 (1H, s)—threeexchangeable protons not observed; m/z (ES+), [M+H]+=504; Chiral HPLC:100% ee, retention time=5.69 min. Stereochemical assignment of theenantiomers was made based on the biological activity against JAK1 inthe Enzyme Inhibition Studies, as shown in Example 66.

The procedure described above for Examples 47 and 48 was repeated usingthe indicated Starting Intermediates and aminopyrazole to give Examples49-59 described in Table 14:

TABLE 14 Starting m/z Yield Example Intermediate Aminopyrazole NMR δ(400 MHz) [M + H]+ % 49¹ 52

Methanol-d4 1.07 (3H, t), 1.89 (2H, m), 2.21 (3H, s), 2.33 (3H, d), 2.59(4H, s), 2.83 (4H, d), 3.20 (1H, dd), 3.88 (3H, s), 7.12 (1H, t), 7.21(1H, d), 7.74 (1H, s), 8.16 (2H, d), 8.37 (1H, s)- three exchangeableprotons not observed 506 38 50¹ 52

Methanol-d4 1.07 (3H, t), 1.89 (2H, m), 2.21 (3H, s), 2.33 (3H, d), 2.59(4H, s), 2.83 (4H, d), 3.20 (1H, dd), 3.88 (3H, s), 7.12 (1H, t), 7.21(1H, d), 7.74 (1H, s), 8.16 (2H, d), 8.37 (1H, s)- three exchangeableprotons not observed 506 38 51^(2,3) 52

DMSO-d6 0.92 (3H, t), 1.65- 1.82 (2H, m), 2.14 (3H, s), 2.34 (4H, m),2.65 (4H, m), 3.16 (1H, t), 3.71 (3H, s), 3.78 (3H, s), 7.05 (1H, t),7.54 (1H, d), 7.66 (1H, s), 8.16 (1H, t), 8.23-8.35 (3H, m), 9.75 (1H,s), 11.36 (1H, s) 522 48 52^(2,3) 52

DMSO-d6 0.92 (3H, t), 1.65- 1.82 (2H, m), 2.14 (3H, s), 2.34 (4H, m),2.65 (4H, m), 3.16 (1H, t), 3.71 (3H, s), 3.78 (3H, s), 7.05 (1H, t),7.54 (1H, d), 7.66 (1H, s), 8.16 (1H, t), 8.23-8.35 (3H, m), 9.75 (1H,s), 11.36 (1H, s) 522 47 53⁴ 53

Methanol-d4 2.21 (3H, s), 2.34 (3H, s), 2.61 (4H, m), 2.83 (2H, s), 2.93(2H, s), 3.43 (3H, s), 3.51 (1H, t), 3.80-3.92 (4H, m), 3.95 (1H, m),7.08-7.21 (2H, m), 7.74 (1H, s), 8.15 (2H, t), 8.38 (1H, s)-threeexchangeable protons not observed 522 26 54⁴ 53

Methanol-d4 2.21 (3H, s), 2.34 (3H, s), 2.61 (4H, m), 2.83 (2H, s), 2.93(2H, s), 3.43 (3H, s), 3.51 (1H, t), 3.80-3.92 (4H, m), 3.95 (1H, m),7.08-7.21 (2H, m), 7.74 (1H, s), 8.15 (2H, t), 8.38 (1H, s)-threeexchangeable protons not observed 522 26 55^(3,5) 54

Methanol-d4 1.31 (3H, t), 1.42 (3H, d), 2.26 (3H, s), 2.35 (3H, s),2.52-2.70 (6H, m), 2.73-2.88 (4H, m), 3.40- 3.42 (1H, m), 3.85 (3H, s),7.06-7.18 (2H, m), 7.77 (1H, s), 7.91 (1H, s), 8.14- 8.19 (2H, m)-threeexchangeable protons not observed 502 19 56⁵ 55

Methanol-d4 1.43 (3H, d), 2.21 (3H, s), 2.34 (3H, s), 2.51-2.91 (8H, m),3.41 (1H, q), 3.88 (3H, s), 7.07- 7.21 (2H, m), 7.74 (1H, s), 8.15 (2H,dd), 8.37 (1H, s)- three exchangeable protons not observed 492 17 57⁵ 59

DMSO-d6 1.27 (3H, d), 2.14 (3H, s), 2.18 (3H, s), 2.26- 2.75 (8H, m),3.25-3.41 (1H, m), 3.77 (3H, s), 7.07 (1H, t), 7.14 (1H, d), 7.40 (1H,d), 7.83 (1H, s), 8.08- 8.36 (3H, m), 8.47 (1H, s), 9.63 (1H, s), 11.36(1H, br s) 474 60 58⁵ 54

Dichloromethane-d2 1.17- 1.44 (6H, m), 2.36 (3H, s), 2.39 (3H, s),2.57-2.90 (8H, m), 3.37 (1H, q), 3.80- 4.08 (5H, m), 6.65 (1H, s), 6.86(1H, d), 7.18 (1H, t), 7.75 (1H, d), 7.87 (1H, s), 8.24 (1H, s), 8.32(1H, d), 9.62 (1H, s), 11.23 (1H, s) 518 50 59⁵ 54

Chloroform-d 1.36-1.50 (9H, m), 2.36 (3H, s), 2.39 (3H, s), 2.55-2.90(8H, m), 3.36 (1H, m), 3.95 (2H, q), 4.32 (2H, q), 6.73 (1H, s), 6.84(1H, d), 7.13 (1H, t), 7.67 (1H, d), 7.90 (1H, s), 8.13-8.40 (2H, m),9.78 (1H, s), 11.17 (1H, br s) 532 82 ¹Chiral separation was performedby chiral-HPLC (Chiralcel OD-H column, isocratic with 10% IPA inhexanes) to give Example 50 (analytical chiral-HPLC: Chiralpak OD-H 5 μsilica, 0.46 × 10 cm column, hexanes (modified with 0.2% IPA):EtOH(90:10) at 1.0 mL/min as the eluent, retention time = 9.02 min) isolatedas the first eluting peak and Example 49 (analytical chiral-HPLC:Chiralpak OD-H 5 μ silica, 0.46 × 10 cm column, hexanes (modified with0.2% IPA):EtOH (90:10) at 1.0 mL/min as the eluent, retention time =11.35 min) isolated as the second eluting peak. Stereochemicalassignment of the enantiomers was made based on the biological activityagainst JAK1 in the Enzyme Inhibition Studies, as shown in Example 66.²Chiral separation was performed by preparative chiral-HPLC(Chiralcel-OD-H, 20 × 250 mm column, isocratic with 10% ethanol inhexanes (modified with 0.2% diethylamine) at 20 mL/min as an eluent) toafford Example 52 (first eluting peak, retention time = 15.87 min) andExample 51 (second eluting peak, retention time = 21.29 min).Stereochemical assignment of the enantiomers was made based on thebiological activity against JAK1 in the Enzyme Inhibition Studies, asshown in Example 66. ³1H NMR analysis was performed using a BrukerAvance 300 (300 MHz) spectrometer. ⁴Chiral separation was performed bypreparative chiral-HPLC (Chiralcel IC column, isocratic with 40% ethanolin hexanes as an eluent) to afford Example 54 (analytical chiral-HPLC:Lux Cellulose-4 3 μ silica, 0.46 × 5 cm column, hexanes (modified with0.1% TEA):EtOH (60:40) at 1.0 mL/min as the eluent, retention time =2.69 min) isolated as the first eluting peak and Example 53 (analyticalchiral-HPLC: Lux Cellulose-4 3 μ silica, 0.46 × 5 cm column, hexanes(modified with 0.1% TEA):EtOH (60:40) at 1.0 mL/min as the eluent,retention time = 3.62 min) isolated as the second eluting peak.Stereochemical assignment of the enantiomers was made based on thebiological activity against JAK1 in the Enzyme Inhibition Studies, asshown in Example 66. ⁵Enantiopure starting material utilized-finalproduct not subject to chiral-HPLC purification.

Examples 60 and 61:(2R)-3-Methoxy-N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamideand(2S)-3-Methoxy-N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide

Diisopropylethylamine (1.25 mL, 7.2 mmol) was added to3-(2-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-7-amine(0.4 g, 1.2 mmol, Intermediate 23), lithium3-methoxy-2-(4-methylpiperazin-1-yl)propanoate (0.72 g, 3.6 mmol,Intermediate 45) and HATU (1.4 g, 3.6 mmol) in DMF (18 mL) at 25° C.under nitrogen. The resulting mixture was stirred at 25° C. for 1 hour.The crude product was purified by preparative HPLC (XBridge Prep C18 OBDcolumn, 5μ silica, 19 mm diameter, 150 mm length), using decreasinglypolar mixtures of water (containing 0.2% ammonia) and acetonitrile aseluents. Fractions containing the desired compound were evaporated todryness to afford racemic3-methoxy-N-(3-(2-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide(0.15 g, 24%) as a white solid; m/z (ES+), [M+H]+=520. The crude productwas purified by preparative chiral-HPLC on a Lux Cellulose-4 column,eluting isocratically with 50% ethanol in isohexane (modified with 0.1%triethylamine) as eluent. The fractions containing the desired compoundwere evaporated to dryness to afford firstly(2S)-3-methoxy-N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide(53 mg, 35%, Example 61) as a white solid; ¹H NMR δ (Methanol-d4, 300MHz) 2.33 (3H, s), 2.60 (4H, s), 2.78-2.99 (4H, m), 3.43 (3H, s), 3.51(1H, t), 3.76-4.00 (8H, m), 7.08-7.22 (3H, m), 7.72 (1H, s), 8.09 (1H,s), 8.19 (1H, d), 8.30 (1H, s)—three exchangeable protons not observed;m/z (ES+), [M+H]+=520; Chiral HPLC: 100% ee, R_(t)=4.072 min; followedby(2R)-3-methoxy-N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide(57 mg, 36%, Example 60) as a white solid; ¹H NMR δ (Methanol-d4, 300MHz) 2.30 (3H, s), 2.57 (4H, s), 2.87-2.80 (4H, m), 3.39 (3H, s), 3.47(1H, t), 3.75-3.98 (8H, m), 7.04-7.18 (3H, m), 7.68 (1H, s), 8.05 (1H,s), 8.15 (1H, d), 8.26 (1H, s)—three exchangeable protons not observed;m/z (ES+), [M+H]+=520; Chiral HPLC: 99.2% ee, R_(t)=5.376 min.Stereochemical assignment of the enantiomers was made based on thebiological activity against JAK1 in the Enzyme Inhibition Studies, asshown in Example 66.

The procedure described above for Examples 60 and 61 was repeated usingthe indicated Starting Intermediates to give the compounds described inTable 15:

TABLE 15 Starting m/z Example Intermediates NMR δ (300 MHz) [M + H]+Yield % 62¹ 30 and 43 DMSO-d6 0.86 (3H, t), 1.20 (3H, t), 532 241.38-1.88 (2H, m), 2.07 (3H, s), 2.26 (7H, m), 2.45-2.74 (4H, m), 3.12(1H, t), 3.59 (3H, s), 4.09 (2H, q), 6.93 (1H, t), 7.47 (1H, d), 7.58(1H, s), 7.77 (1H, s), 7.92 (1H, s), 8.08 (1H, s), 8.18 (1H, br s), 9.58(1H, s), 11.13 (1H, s) 63¹ 30 and 43 DMSO-d6 0.86 (3H, t), 1.20 (3H, t),532 16 1.45-1.76 (2H, m), 2.07 (3H, s), 2.26 (7H, s) 2.54-2.73 (4H, m),3.10 (1H, t), 3.59 (3H, s), 4.09 (2H, q), 6.94 (1H, s), 7.45 (1H, d),7.58 (1H, s), 7.78 (1H, s), 7.91 (1H, s), 8.08 (1H, s), 8.18 (1H, br s)9.55 (1H, s), 11.10 (1H, s) 64² 30 and 45 DMSO-d6 1.19 (3H, t), 2.10(3H, s), 548 32 2.33-2.38 (7H, m), 2.56-2.72 (4H, m), 3.34 (3H, s), 3.64(1H, t), 3.69- 3.73 (5H, m), 4.09 (2H, q), 6.94 (1H, t), 7.39 (1H, d),7.58 (1H, s), 7.80 (1H, s), 7.91(1H, d), 8.08 (1H, s), 8.18 (1H, br s),9.69 (1H, s), 11.08 (1H, br s) 65² 30 and 45 DMSO-d6 1.27 (3H, t), 2.15(3H, s), 548 30 2.34-2.38 (7H, m), 2.60-2.76 (4H, m), 3.33 (3H, s), 3.69(1H, t), 3.68- 3.73 (5H, m), 4.16 (2H, q), 6.96 (1H, t), 7.45 (1H, d),7.60 (1H, s), 7.83 (1H, s), 7.90 (1H, s), 8.10 (1H, s), 8.18 (1H, br s),9.71 (1H, br s), 11.10 (1H, br s) ¹Chiral separation was performed bypreparative chiral-SFC (Chiralcel OD, 5 μm, 21 × 250 mm) elutingisocratically with 20% MeOH (modified with 0.1% dimethylethylamine) at75 mL/min at 40° C., to afford Example 63 (first eluting peak, retentiontime = 7.89 min) and Example 62 (second eluting peak, retention time =8.81 min). Stereochemical assignment of the enantiomers was made basedon the biological activity against JAK1 in the Enzyme InhibitionStudies, as shown in Example 66. ²Chiral separation was performed bypreparative chiral-SFC (Chiralcel OD, 5 μm, 21 × 250 mm) elutingisocratically with 25% MeOH (modified with 0.1% dimethylethylamine) at75 mL/min at 40° C., to afford Example 65 (first eluting peak, retentiontime = 4.84 min) and Example 64 (second eluting peak, retention time =5.95 min). Stereochemical assignment of the enantiomers was made basedon the biological activity against JAK1 in the Enzyme InhibitionStudies, as shown in Example 66.

Example 66: Enzyme Inhibition Studies

Enzyme inhibition studies were performed using recombinant JAK1 (aminoacids 866-1154, Life Technologies, #PV4774, Carlsbad, Calif.), JAK2(amino acids 831-1132), or JAK3 (amino acids 781-1124) under bufferconditions of 50 mM HEPES pH 7.3, 1 mM DTT, 0.01% Tween® 20, 50 μg/mLBSA, and 10 mM MgCl₂. JAK enzyme was expressed as an N-terminal GSTfusion in insect cells and purified by glutathione-affinity andsize-exclusion chromatographies. Enzymes were assayed both at theirrespective ATP Km (JAK1: 55 μM, JAK2: 15 μM, JAK3: 3 μM) and theapproximated high end of physiological ATP concentration of 5 mM, in thepresence of inhibitor dosed at 30, 3, 0.3, 0.03, 0.003 and 0 μM finaltest concentrations. For JAK1, 6 nM of enzyme (for Km ATP assay) or 4 nMenzyme (for high ATP assay) was incubated with 1.5 μM peptide substrate(FITC-C6-KKHTDDGYMPMSPGVA-NH2 (SEQ ID NO:1), Intonation, Boston, Mass.).For JAK2, 0.8 nM of enzyme (for Km ATP assay) or 0.3 nM enzyme (for highATP assay) was incubated with 1.5 μM peptide substrate(5FAM-GEEPLYWSFPAKKK-NH2 (SEQ ID NO:2), Intonation, Boston, Mass.). ForJAK3, 0.2 nM of enzyme (for Km ATP assay) or 0.1 nM enzyme (for high ATPassay) was incubated with 1.5 μM peptide substrate(5FAM-GEEPLYWSFPAKKK-NH2 (SEQ ID NO:2), Intonation, Boston, Mass.).Phosphorylated and unphosphorylated peptides were separated andquantified by a Caliper LC3000 system (Caliper Life Sciences, MA) forcalculating percent inhibition. The results of this assay are shown inTable 16 and indicate that the compounds of Formula (I), (Ia), (Ib) andTable 1 exhibit preferential inhibition of JAK1 over JAK2 (in many casesdemonstrating over 100 times selectivity for inhibition of JAK1 vs.JAK2).

Example 67: Cellular pSTAT3 Assay

NCI-H1975 cells were plated onto Costar #3701 96 or 384 welltissue-culture treated plates at 5,000 cells/well in 30 uL medium (RPMI,10% FBS, supplemented with L-glutamine) and incubated overnight at 37°C. in 5% CO₂. Phospho STAT3 signal was quantitated utilizing CellSignaling Technology #7146B Pathscan 98hosphor STAT3 antibody pair kit,following manufacturer's instructions.

Cells were dosed with compound and incubated at 37° C. in 5% CO₂ for 2hours, after which medium and compound were aspirated and cells lysedwith 35 uL cold 1× Cell Signaling Lysis buffer and chilled at 4° C. for1-2 hours. Lysate was incubated on STAT3 capture plates at 4° C.overnight, washed 3× with Tris-Buffered Saline with 0.05% Tween® 20(TBST), then 99 phosphor STAT3 detection antibody was applied for 2hours. Following washing with TBST (3×), HRP-secondary antibody wasapplied for 2 hours. After additional washing, signal was detected usingTMB and Stop solution and read at 450 nm using Tecan Infinite M100. IC₅₀values (the concentration that causes 50% inhibition) were calculated byplotting percent inhibition of the phosphor-signal relative to untreatedsample (maximum signal) and positive control treated sample (maximuminhibition/minimum signal), using Xlfit4 version 4.2.2 for MicrosoftExcel. The results of this assay, shown in Table 16, demonstrate goodcorrelation between cellular inhibition of STAT3 phosphorylation inNCI-H1975 cells and JAK1 enzyme inhibition.

TABLE 16 JAK1 JAK2 JAK3 NCI-H1975 pSTAT3 Example (IC₅₀, μM) (IC₅₀, μM)(IC₅₀, μM) (IC₅₀, μM)  1 0.847 >30 >30 0.643  2 0.085 12.8 >30 0.227  30.191 26.8 >30 0.302  4 0.043 6.57 >30 0.0986  5 0.024 10.4 >30 0.0872 6 0.030 9.62 >30 0.111  7a 0.359 >30 >30 0.509  7b 3.60 >30 >30 >3  80.110 23.6 >30 0.191  9 0.426 >30 >30 0.594 10a 0.846 >30 >30 0.531 10b7.60 >30 >30 >3 11a 0.040 >30 >30 0.209 11b 1.85 >30 >30 2.28 12 0.06822.6 >30 0.246 13 0.166 >30 >30 0.222 14 0.009 6.39 >30 0.0703 15 0.0072.53 >30 0.131 16 0.019 6.24 >30 0.105 17 0.107 18.1 >30 0.229 18 0.05717.3 >30 0.175 19 0.296 >30 >30 0.470 20 0.051 17.2 >30 0.184 210.184 >30 >30 0.703 22 0.490 >30 >30 0.550 23 0.029 25.7 >30 0.410 240.113 >30 >30 0.370 25 0.019 6.62 >30 0.115 26 0.069 16.7 >30 0.256 270.575 >30 >30 0.609 28 0.106 11.8 >30 0.100 29 0.097 20.4 >30 0.227 300.304 >30 >30 0.359 31a 0.015 19.8 >30 0.153 31b 0.454 >30 >30 0.330 320.073 >14.7 >30 0.161 33 0.272 >30 >30 0.308 34 0.010 5.37 >30 0.128 350.020 17.0 >30 0.153 36 0.007 1.76 19.1 0.0579 37 0.008 1.58 15.4 0.094238 0.013 6.48 >30 0.108 39 0.055 25.5 >30 0.191 40 0.024 8.93 >30 0.16041 <0.005 2.58 >30 0.0923 42 0.106 21.1 >30 0.172 43 0.079 21.1 >300.176 44 <0.004 1.95 >30 0.0577 45 <0.003 0.790 >30 0.0603 460.986 >30 >30 1.28 47 0.013 6.95 >30 0.136 48 1.21 >30 >30 0.863 49<0.004 1.77 >30 0.0751 50 0.265 24.1 >30 0.999 51 <0.003 3.19 >30 0.11152 0.296 >30 >30 0.548 53 <0.003 0.322 >30 0.0566 54 1.67 >30 >30 >3 550.027 4.22 >30 0.116 56 0.028 5.15 >30 0.126 57 0.069 9.26 >30 0.155 580.017 8.85 >30 0.106 59 0.069 >30 >30 0.245 60 0.004 1.53 >30 0.0973 612.90 >30 >30 1.27 62 <0.006 5.01 >30 0.104 63 0.192 >30 >30 0.433 64<0.005 2.04 >30 0.112 65 2.53 >30 >30 1.03

Example 68: Solid Forms of(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamideMethods

X-Ray Powder Diffraction (XRPD) Analysis

XRPD analysis was performed using a Bruker D4 (or D8) diffractometer,which is commercially available from Bruker AXS Inc™ (Madison, Wis.).The XRPD spectra were obtained by mounting a sample (approximately 20mg) of the material for analysis on a single silicon crystal wafer mount(e.g., a Bruker silicon zero background X-ray diffraction sample holder)and spreading out the sample into a thin layer with the aid of amicroscope slide. The sample was spun at 30 revolutions per minute (toimprove counting statistics) and irradiated with X-rays generated by acopper long-fine focus tube operated at 40 kV and 40 mA with awavelength of 1.5406 angstroms (i.e., about 1.54 angstroms). The samplewas exposed for 1 second per 0.02 degree 2-theta increment (continuousscan mode) over the range 5 degrees (or 2 degrees) to 40 degrees 2-thetain theta-theta mode. The running time was ˜17 min for D4 and ˜15 min forD8.

XRPD 2θ values may vary with a reasonable range, e.g., in the range±0.2°and that XRPD intensities may vary when measured for essentially thesame crystalline form for a variety of reasons including, for example,preferred orientation. Principles of XRPD are described in publications,such as, for example, Giacovazzo, C. et al. (1995), Fundamentals ofCrystallography, Oxford University Press; Jenkins, R. and Snyder, R. L.(1996), Introduction to X-Ray Powder Diffractometry, John Wiley & Sons,New York; and Klug, H. P. & Alexander, L. E. (1974), X-ray DiffractionProcedures, John Wiley and Sons, New York.

DSC Analysis

DSC analysis was performed on samples prepared according to standardmethods using a Q SERIES™ Q1000 DSC calorimeter available from TAINSTRUMENTS® (New Castle, Del.). A sample (approximately 2 mg) wasweighed into an aluminum sample pan and transferred to the DSC. Theinstrument was purged with nitrogen at 50 mL/min and data collectedbetween 22° C. and 300° C., using a dynamic heating rate of 10°C./minute. Thermal data was analyzed using standard software, e.g.,Universal v.4.5A from TA INSTRUMENTS®.

Thermogravimetry Analysis (TGA)

TGA was performed on samples prepared according to standard methodsusing a Q SERIES™ Q5000 thermogravimetry analyzer available from TAInstruments INSTRUMENTS® (New Castle, Del.). A sample (approximately 5mg) was placed into an aluminum sample pan and transferred to the TGAfurnace. The instrument was purged with nitrogen at 50 mL/min and datacollected between 25° C. and 300° C., using a dynamic heating rate of10° C./minute. Thermal data was analyzed using standard software, e.g.,Universal v.4.5A from TA INSTRUMENTS®.

Example 68A: Form A(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide

Method 1:

50 mg of off-white amorphous(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidewas dissolved in 0.4 ml of TBME in a 4 mL vial. The solid precipitatedout from the solution after 30 minutes. The slurry was stirred underambient conditions overnight. The resulting white solid material wasidentified as Form A by XRPD analysis.

Method 2:

500 mg of amorphous(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamideand approximately 50 mg of crystalline seeds obtained from Method 1 weremixed in a 20 mL vial. To the mixture, 5 mL of TBME was added to form aslurry. The slurry was stirred under ambient conditions overnight and ahomogenous slurry formed. The slurry was filtered, and the resultingsolid was washed with TBME and dried in air. 498 mg of a whitecrystalline solid was obtained and identified as Form A by XRPDanalysis.

Form A (Method 2) was analyzed by XRPD and the results are tabulatedbelow (Table 17) and shown in FIG. 1.

TABLE 17 Angle (2θ ± 0.2°) Intensity (%) 21.6 100.0 6.4 74.9 16.4 56.58.7 54.2 20.4 45.8 7.9 42.8 22.2 36.2 18.8 34.6 16.8 29.6 9.3 29.2 20.126.3 16.1 24.5 19.8 23.2 26.5 22.1 13.8 20.9 19.2 20.8 13.2 19.5 12.017.2 23.8 16.9 21.1 15.4 25.4 14.3 28.5 14.3 12.9 13.7 8.3 12.7 10.911.7 25.9 11.7 24.4 11.5 22.7 11.4 32.0 10.9 15.7 10.7 14.8 10.1 25.09.2 27.0 8.7 9.9 8.2 11.6 8.2 29.2 7.7 29.9 7.6 17.4 7.4 17.8 7.4 27.87.2 30.2 6.8 32.6 6.2 31.1 5.5

Form A (Method 2) was analyzed by thermal techniques. DSC analysisindicated that Form A has an endotherm event of desolvation with anonset at 110° C. and a peak at 113° C. TGA indicated that Form Aexhibits a mass loss of about 7.8% upon heating from about 25° C. toabout 150° C. A representative DSC/TGA thermogram of Form A is shown inFIG. 2.

Example 68B: Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide

Approximately 100 mg of light yellow amorphous(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidewas suspended 0.5 mL of toluene with Form B seeds. The slurry wasstirred at room temperature overnight. The slurry was evaporated anddried in the ambient condition. A white crystalline solid was obtainedand identified as Form B by XRPD.

Form B was analyzed by XRPD and the results are tabulated below (Table18) and shown in FIG. 3.

TABLE 18 Angle (2θ ± 0.2°) Intensity (%) 21.6 100.0 6.3 93.7 8.8 72.219.0 53.5 8.0 53.1 16.3 47.3 9.5 43.4 22.4 41.2 20.4 34.8 19.7 30.2 13.927.1 26.4 26.7 28.6 25.2 16.7 24.7 15.9 19.5 10.8 19.0 11.9 18.5 13.418.4 23.9 17.6 31.8 15.8 24.4 14.7 25.5 14.6 25.1 14.3 28.1 13.5 32.712.9 14.6 12.6 29.8 11.9 37.5 11.7 29.3 10.6 15.0 10.4

Single crystals of Form B were obtained from slow evaporation of atoluene solution. Single crystal structure analysis confirmed that FormB is a hemi-toluene solvate form. Crystallographic data: Space grouptriclinic P1, unit cell dimensions: a=14.1919(8) Å, b=14.2964(8) Å,c=14.7632(8) Å, α=82.283(1)°, β=77.596(1)°, γ=85.567(1)°, V=2895.3(3)Å³.

Form B was analyzed by thermal techniques. DSC analysis indicated thatForm B has an endotherm event of desolvation with an onset at 112° C.and a peak at 117° C. TGA indicated that Form B exhibits a mass loss ofabout 10.0% upon heating from about 25° C. to about 200° C. Arepresentative DSC/TGA thermogram of Form B is shown in FIG. 4.

Example 68C: Form C(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide

Approximately 100 mg of amorphous(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidewas dissolved in 1 mL of isopropyl acetate to yield a clear solution.The solution was placed in the freezer overnight and a solidprecipitated out. The slurry was stirred at room temperature for 4 hoursto obtain a white solid in the slurry. The slurry was evaporated anddried under ambient condition. A white crystalline solid was obtainedand was identified as Form C by XRPD.

Form C was analyzed by XRPD and the results are tabulated below (Table19) and shown in FIG. 5.

TABLE 19 Angle (2θ ± 0.2°) Intensity (%) 8.7 100.0 21.5 68.0 6.3 58.616.3 53.8 22.2 31.5 18.9 30.3 7.9 28.3 20.4 26.3 13.8 22.0 19.7 21.526.4 19.3 9.3 18.1 16.6 12.6 23.6 12.1 19.9 11.8 11.9 11.3 13.2 11.128.4 11.1 25.3 10.7 16.0 9.3 18.4 8.9 31.8 8.1 26.0 8.0 24.2 7.9 10.76.8 17.5 6.8 20.9 6.6 12.8 6.3 29.8 6.0 15.7 5.8 26.9 5.8 14.7 5.5

Form C was analyzed by thermal techniques. DSC analysis indicated thatForm C has an endotherm event of desolvation with an onset at 112° C.and a peak at 114° C. TGA indicated that Form C exhibits a mass loss ofabout 9.2% upon heating from about 25° C. to about 175° C. Arepresentative DSC/TGA thermogram of Form C is shown in FIG. 6.

Example 68D: Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide

Method 1:

Approximately 100 mg of light yellow amorphous(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidewas dissolved in 1 ml of EtOAC to get a clear solution. The solution wasplaced in the freezer overnight and solid was precipitated out. Theslurry was stirred at room temperature for 4 hours to get a white solidin the slurry. The slurry was evaporated and dried under ambientconditions. An off-white crystalline solid was obtained and identifiedas Form D by XRPD analysis.

Method 2:

5.01 g of light brown amorphous(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidewas dissolved in 10 mL of EtOAC to yield a light brown solution and abrown gel. 0.10 g of(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide-FormD seed from Method 1 was added and the solution became a wet cake within5 minutes. 10 mL of EtOAc was added to form a slurry. The slurry wasstirred under ambient conditions overnight. The brown gel disappeared toobtain a slurry of an off-white solid with brown solution. The slurrywas filtered, and the solid was washed twice with EtOAc. The off-whitesolid was dried under ambient conditions. 4.78 g of an off-whitecrystalline solid was obtained and identified as Form D by XRPDanalysis.

Form D (Method 2) was analyzed by XRPD and the results are tabulatedbelow (Table 20) and shown in FIG. 7.

TABLE 20 Angle (2θ ± 0.2°) Intensity (%) 21.8 100.0 6.4 74.8 16.6 59.28.9 50.1 22.5 48.3 8.1 43.0 19.1 40.4 19.9 40.0 20.6 36.8 26.6 30.2 9.526.6 16.0 24.8 14.0 20.9 24.1 19.8 28.9 19.2 18.6 19.0 13.4 18.8 25.817.1 25.4 15.4 26.3 14.8 32.1 13.5 10.9 12.6 12.1 12.2 14.8 12.2 28.411.9 30.0 11.4 33.0 11.4 38.9 10.2 36.5 10.1 15.2 9.3

Single crystals of Form D were obtained from slow evaporation of anEtOAc solution. Single crystal structure analysis confirmed that Form Dis a hemi-EtOAc solvate form. Crystallographic data: Space grouptriclinic P1, unit cell dimensions: a=14.051(2) Å, b=14.289(2) Å,c=14.756(2) Å, α=81.174(5)°, β=77.476(5)°, γ=85.331(6)°, V=2854.5(8) Å³.

Form D was analyzed by thermal techniques. DSC analysis indicated thatForm D has an endotherm event of desolvation with an onset at 116° C.and a peak at 119° C. TGA indicated that Form D exhibits a mass loss ofabout 8.0% upon heating from about 25° C. to about 200° C. Arepresentative DSC/TGA thermogram of Form D is shown in FIG. 8.

Example 68E: Form A(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamideSaccharine Salt

25.1 mg of(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide(0.05 mmol) was dissolved in 1 mL of MeOH, and 2.0 mL (0.10 mmol) of0.05 M of saccharin MeOH solution was added to yield a light yellowsolution. To the solution, 1 mL of ACN was added and the resultingsolution was evaporated under ambient conditions. A partial yellowcrystalline material was obtained. Approximately 10 mg of the resultingmaterial was dissolved in 2 mL of ACN and the resulting yellow solutionwas evaporated slowly to obtain yellow needle crystals identified asForm A(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharin salt by XRPD analysis.

Form A of the saccharin salt was analyzed by XRPD and the results aretabulated below (Table 21) and shown in FIG. 9.

TABLE 21 Angle (2θ ± 0.2°) Intensity (%) 14.4 100.0 10.7 52.0 7.1 48.121.4 44.3 10.1 42.1 8.5 38.9 8.2 36.5 17.3 36.5 16.3 27.3 9.4 26.0 11.625.2 17.8 23.0 20.8 22.5 20.1 18.2 18.5 16.8 18.8 16.7 25.4 16.3 24.915.9 21.8 15.6 27.4 15.2 27.8 15.2 26.7 13.9 24.4 13.6 23.4 13.4 15.413.3 28.9 13.1 30.4 12.2 35.3 11.9 31.1 11.2 12.5 11.1 19.4 10.5

Form A of the saccharin salt was analyzed by thermal techniques. DSCanalysis indicated that Form A has an endotherm event of melting pointwith an onset at 163° C. and a peak at 169° C. TGA indicated that Form Aexhibits a mass loss of about 3.1% upon heating from about 25° C. toabout 150° C. A representative DSC/TGA thermogram of Form D is shown inFIG. 10.

Example 68F: Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamideSaccharine Salt

246 mg of light yellow(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide(0.5 mmol) and 184 mg (1.0 mmol) of saccharine was dissolved in 3 mL ofacetonitrile and 1 mL of MeOH to yield a clear yellow solution. Thesolution was evaporated to have about 1.0 mL of solvent and a yellowcrystalline material precipitated. The suspension was stirred for 30minutes and filtered. The solid was dried under ambient conditions. Ayellow crystal material was obtained and identified as Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt by XRPD.

Form B of the saccharin salt was analyzed by XRPD and the results aretabulated below (Table 22) and shown in FIG. 11.

TABLE 22 Angle (2θ ± 0.2°) Intensity (%) 6.6 100.0 13.4 99.8 25.3 85.818.1 82.7 8.0 76.8 17.2 71.0 9.1 65.3 21.8 64.2 9.9 64.0 26.0 58.9 16.458.7 26.4 57.9 21.3 57.3 20.2 54.5 27.9 48.6 14.7 48.1 16.2 47.6 24.146.8 20.4 45.0 23.0 45.0 24.7 43.3 18.7 42.4 11.0 39.9 15.2 39.2 15.735.1 29.7 34.4

Form B of the saccharin salt was analyzed by thermal techniques. DSCanalysis indicated that Form B has a broad endotherm event ofdesolvation with a peak at 53° C., followed by two endotherm events, onewith an onset at 153° C. and a peak at 162° C. and the other with anonset at 176° C. and a peak at 182° C. TGA indicated that Form Bexhibits a mass loss of about 2.7% upon heating from about 25° C. toabout 100° C. A representative DSC/TGA thermogram of Form B is shown inFIG. 12.

Example 68G: Form C(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamideSaccharine Salt

Approximately 200 mg of Form B(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharin salt was slurried in acetone for 3 days, and the resultingslurry was evaporated under ambient conditions. A yellow crystalmaterial was obtained and identified as Form C(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine salt by XRPD.

Form C of the saccharin salt was analyzed by XRPD and the results aretabulated below (Table 23) and shown in FIG. 13.

TABLE 23 Angle (2θ ± 0.2°) Intensity (%) 5.5 100.0 17.0 82.5 26.3 82.08.2 80.3 14.9 76.9 24.9 73.4 16.0 72.9 14.4 70.6 18.1 57.6 12.4 55.8 9.453.0 20.7 52.4 28.0 46.8 19.2 46.6 19.8 45.3 21.5 43.0 23.8 40.2 15.436.7 13.4 33.1 22.8 32.6 29.8 28.0

Example 68H: Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamideSaccharine Salt

Approximately 15 mg of Form B or Form C(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharin salt was slurried in 0.5 mL of water. The resulting slurry wasdried in the sample holder and was measured by XRPD analysis and Form D(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharin salt was identified.

Form D of the saccharin salt was analyzed by XRPD and the results aretabulated below (Table 24) and shown in FIG. 14.

TABLE 24 Angle (2θ ± 0.2°) Intensity (%) 19.2 100.0 5.4 96.7 20.1 95.76.8 93.7 15.4 83.0 7.7 74.1 20.8 72.1 13.8 66.8 17.3 61.4 13.4 58.5 23.158.3 10.4 43.4 9.3 42.5 14.3 33.4 16.9 30.9 11.5 27.2 27.2 22.8 26.221.1

Example 68I: Form E(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamideSaccharine Salt

About 15 mg of Form C(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharin salt was slurried in 0.5 mL of EtOH. The resulting slurry wasevaporated under ambient conditions. A yellow powder was obtained andwas identified as Form E(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharin salt by XRPD analysis.

Form E of the saccharin salt was analyzed by XRPD and the results aretabulated below (Table 25) and shown in FIG. 15.

TABLE 25 Angle (2θ ± 0.2°) Intensity (%) 15.4 100.0 19.3 96.9 5.5 86.414.7 78.5 23.2 76.8 6.7 73.3 20.1 71.0 7.8 66.8 26.3 58.4 17.7 53.3 25.253.0 18.2 52.5 24.6 52.0 24.0 50.3 13.5 50.1 27.3 49.4 9.3 45.7 17.144.5 21.4 42.1 16.4 37.2 29.2 33.9 11.8 33.5

Example 68J:(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamideSaccharine Hydrochloride Salt

249 mg (0.50 mmol) of(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidewas dissolved in 4 mL of MeOH to yield a light brown solution. 0.5 ml of1N HCl aqueous solution (0.50 mmol) was added and the color of thesolution turned to yellow. To the yellow solution, 0.5 mmol ofsaccharine was added, and the saccharine gradually dissolved in thesolution to yield a yellow solution. The solution was evaporated underambient conditions to dry. The resulting solid was slurried in 4 mL ofacetone overnight, then filtered and washed with acetone. The yellowsolid was dried in air and identified as(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidesaccharine hydrochloride salt by XRPD analysis.

The saccharin hydrochloride salt was analyzed by XRPD and the resultsare tabulated below (Table 26) and shown in FIG. 16.

TABLE 26 Angle (2θ ± 0.2°) Intensity (%) 13.7 100.0 20.2 84.0 26.0 82.717.3 80.8 8.4 59.9 25.4 57.4 20.6 54.8 27.6 53.9 10.6 52.1 26.6 49.418.4 48.5 20.9 47.1 24.3 44.8 15.0 43.9 15.7 42.3 12.9 39.7 25.1 39.318.8 39.2 12.5 37.7 22.6 36.2 16.1 33.1 29.4 33.1 23.3 32.9 27.2 32.928.9 32.3 21.7 31.0 21.2 27.1 32.0 26.3 22.2 22.9 32.8 21.5 33.6 21.129.9 19.7 30.5 19.6 31.2 18.8

Example 68K:(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamideNapadosylic Salt

35.8 mg of off-white amorphous(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidewas dissolved in 0.8 mL of EtOH:water mixture (70:30), and 29.02 mg ofnapadisylic acid tetrahydrate was dissolved in 0.5 mL of the samesolvent. The counter ion solution was added to the solution of(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidedropwise and a yellow precipitate was obtained. The slurry was stirredat the ambient condition for overnight. The slurry was filtered toobtain a crystalline material.

The napadisylic acid salt was analyzed by XRPD and the results aretabulated below (Table 27) and shown in FIG. 17.

TABLE 27 Angle (2θ ± 0.2°) Intensity (%) 5.2 100.0 10.4 78.5 7.8 74.018.3 68.1 17.3 64.1 15.0 59.3 22.1 58.7 25.6 58.7 20.9 58.2 15.6 57.420.3 56.3 16.9 52.9 16.1 51.1 26.5 46.9 24.2 46.6 21.2 46.6 24.0 44.227.5 42.7 23.2 42.5 19.9 41.6 14.2 39.0 7.2 38.4 12.1 32.2 13.5 32.211.3 31.0 30.6 24.3 31.2 23.8

Example 68L:(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamideTrimesic Salt

30 mg of off-white amorphous(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidewas dissolved in 0.5 mL of EtOH:water mixture (70:30), and 14.16 mg oftrimesic acid was dissolved in 0.6 mL of the same solvent. The counterion solution was added to the solution of(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamidedropwise. The resulting solution was subjected to slow evaporation andisolated by centrifugation.

The trimesic acid salt was analyzed by XRPD and the results aretabulated below (Table 28) and shown in FIG. 18.

TABLE 28 Angle (2θ ± 0.2°) Intensity (%) 4.2 100.0 12.4 66.3 7.8 63.025.1 27.8 24.9 27.3 2.1 20.6 27.5 19.1 12.1 16.3 15.7 16.2 10.6 14.426.1 13.8 16.5 13.2 15.9 12.8 8.3 12.6 19.8 11.8 20.7 11.8 25.7 11.429.1 11.0 8.7 10.7 22.1 10.4 17.5 10.0 23.0 9.9 19.2 9.0 13.9 9.0 23.58.9 23.8 8.9 28.1 8.2 26.9 8.1 21.2 7.6 14.3 7.4 18.2 7.4 22.7 7.4 15.27.3 17.0 6.9 37.7 6.5 18.6 6.3 33.2 6.1 34.3 6.1 39.3 5.6 39.3 5.4 30.65.3 11.3 5.0 31.2 4.9

Example 69: Example 32 in Combination with Osimertinib—In Vivo Efficacyand Pharmacodynamics in the H1975 Xenograft Model

Summary:

NCI-H1975 tumor xenografts were grown subcutaneously in female nudemice. The mice were treated by oral dosing with vehicle, Example 32, theEGFR inhibitor osimertinib (AZD9291, TAGRISSO™), an irreversibleinhibitor of T790M mutant EGFR, or combinations of Example 32 andosimertinib. Average tumor size at the start of treatment (10 days afterimplant) was 189 mm³. Tumor volume was measured twice a week. Additionalmice were treated with the same doses of Example 32 and osimertinib, andtumors and plasma harvested after one day of treatment, for analysis ofpSTAT3 (Y705) levels in tumors and drugs levels in plasma.

The combination of Example 32 with osimertinib resulted in enhancedantitumor activity, compared to treatment with osimertinib alone. Therewas no significant antitumor activity observed after treatment withExample 32 alone. The enhanced antitumor activity of the combinationcorrelated with pSTAT3 knockdown by Example 32, consistent with a rolefor JAK/STAT signaling in escape from pEGFR inhibition.

Osimertinib, an irreversible inhibitor of T790M mutant EGFR, overcomesT790M-mediated resistance to EGFR inhibitors such as gefitinib anderlotinib in lung cancer. This study was carried out to evaluate theability of Example 32 to enhance the antitumor response to osimertinibin mice bearing subcutaneous NCI-H1975 tumor xenografts. The EGFR genein the NCI-H1975 tumors is mutated at L858R and also contains the T790Mresistance mutation.

Materials and Methods:

NCI-H1975 cells (a human NSCLC cell line with L858R and T790M mutationsin the EGFR gene) tumor cells were implanted subcutaneously in femaleNCr nude mice (Taconic Laboratories), 3×10⁶ cells/mouse. Ten days aftercell implantation, mice were randomized into 10 groups (6-8 mice/group,average tumor volume 189 mm³, range 152-250 mm³), and were dosed orallywith either vehicle (20% captisol), Example 32 as a single agent (12.5mg/kg, 25 mg/kg, 50 mg/kg), osimertinib as a single agent (2.5 mg/kg),or combinations of Example 32 and osimertinib (osimertinib at 2.5 mg/kgand Example 32 at 12.5 mg/kg, 25 mg/kg and 50 mg/kg) for 18 days. Someof the mice from the tumor implant that were not randomized into thesegroups were treated for a single day with these compounds forpharmacokinetic and pharmacodynamic analysis (tumor and plasma collectedfor analysis of drug levels in plasma and pSTAT3 (Y705) levels in tumorlysates, samples collected 2, 8 and 24 hours after the AM dose). Tumorlength and width were measured by caliper, and tumor volume calculatedusing the formula volume=(length×width²)*π/6. Example 32 was formulatedin water, adjusted to pH 2 with methane sulfonic acid. Osimertinib wasformulated in 0.5% HPMC in water. All formulations were administered byoral gavage, at a volume of 5 ml/kg. Osimertinib was dosed QD (AM),Example 32 was dosed BID (AM and PM, 8 hours apart). In the groups thatwere dosed with osimertinib in combination with Example 32, the AMdosing of osimertinib occurred 3 hours before Example 32 to minimizeexposure interactions. AZD1480 (5-chloro-N2-[(1S)-1-(5-fluoro-2-pyrimidinyl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)-2,4-pyrimidinediamine,see U.S. Patent Application Publication No. US20080287475), a JAK1/2inhibitor and a positive control for 100% pSTAT3 knockdown in thepharmacokinetic/pharmacodynamic experiment was formulated in 0.5%HPMC/0.1% Tween® 80 in water, and administered by oral gavage at avolume of 5 ml/kg. Y705 phosphorylated STAT3 (pSTAT3) levels weremeasured in tumor lysates using a sandwich ELISA (PathScan Phospho-STAT3Sandwich ELISA Kit, CST #7146B). Drug levels in plasma were measured byLC/MS, using a Linear Ion Trap Quadrupole LC/MS/MS Mass Spectrometer(QTRAP 5500 model 1024945-BB, AB Sciex Instruments), with separation ona Waters Xbridge C18 column.

Results:

The addition of Example 32 enhanced the antitumor activity ofosimertinib, compared to treatment with osimertinib alone. Example 32administered as a single agent had only weak antitumor activity relativeto vehicle control treatment (FIG. 19). The enhancement of antitumoractivity increased with increasing dose of Example 32 (12.5 mg/kg up to50 mg/kg). At the last day of treatment, the inhibition of tumor growthof all of the combination treatments was statistically significant(p<0.05), compared to single agent osimertinib (Table 29). Alltreatments were well tolerated, with no significant weight loss (FIG.20) or other outward signs observed over the course of treatment. A dosedependent increase in pSTAT3 knockdown was observed with increasing doseof Example 32 (FIG. 21), which correlated with an increasing level ofExample 32 in plasma.

TABLE 29 p values For Antitumor Activity of Osimertinib and Example 32combinations, After 18 Days of Treatment vs. Osimertinib vs. VehicleTreatment Single Agent^(a) Control^(b) osimertinib, 2.5 mg/kg QD —0.0002 osimertinib, 2.5 mg/kg QD + 0.0027 <0.0001 Example 32, 12.5 mg/kgBID osimertinib, 2.5 mg/kg QD + <0.0001 <0.0001 Example 32, 25 mg/kg BIDosimertinib, 2.5 mg/kg QD + <0.0001 <0.0001 Example 32, 50 mg/kg BID^(a)Two-sided test ^(b)One-sided test

Conclusion:

The increased antitumor activity of the osimertinib in combination withExample 32 compared to single agent osimertinib, and the correlationwith pSTAT3 knockdown by Example 32, is consistent with a role for STAT3signaling in escape from, or resistance to, EGFR inhibition in thismodel of non-small cell lung cancer. This conclusion is furthersupported by the correlation of increased pSTAT3 knockdown withincreased combination antitumor activity over the dose range of Example32. The results support the hypothesis that inhibition of STAT3signaling can enhance the antitumor activity of an EGFR inhibitor inT790M EGFR mutant NSCLC.

Example 70: Example 32 in Combination with Gefitinib—In Vivo Efficacyand Pharmacodynamics in the PC-9 Xenograft Model

Summary

PC9 tumor xenografts were grown subcutaneously in female nude mice. Themice were treated, by oral dosing, with vehicle, Example 32, the EGFRinhibitor gefitinib, or combinations of Example 32 and gefitinib.Average tumor size at the start of treatment was 240 mm³. Tumor volumewas measured twice a week. At the end of treatment (21 days), tumorswere harvested for analysis of pSTAT3 (Y705) levels.

The combination of Example 32 and gefitinib resulted in enhancedantitumor activity, compared to treatment with gefitinib alone. Theenhanced antitumor activity of the combination correlated with pSTAT3knockdown by Example 32, consistent with a role for JAK/STAT signalingin escape from pEGFR inhibition.

Gefitinib is an inhibitor of mutant EGFR, with activity in non-smallcell lung cancer patients bearing the del19 and L858R mutations in EGFR.This study was carried out to evaluate the ability of Example 32 toenhance the antitumor response to gefitinib in mice bearing subcutaneousPC-9 tumor xenografts. The EGFR gene in PC-9 tumors contains the del19mutation.

Materials and Methods:

PC-9 cells (a human NSCLC cell line with the EGFR del19 mutation), wereimplanted subcutaneously in female CB17-SCID mice (Charles RiverLaboratories), 2×10⁶ cells/mouse. Thirty-two days after cellimplantation, the mice were randomized into 5 groups (7 mice/group,average tumor volume 240 mm³, range 204-298 mm³). Mice were dosed orallywith either vehicle (1% Tween® 80, QD), gefitinib as a single agent orcombinations of gefitinib and Example 32, for 21 days at the doses andschedules indicated in FIGS. 22 and 23. On the last day of treatment,tumors were collected (2, 8 and 24 hours after the AM dose) for analysisof pSTAT3 (Y705) levels in tumor lysates. Tumor length and width weremeasured by caliper, and tumor volume calculated using the formulavolume=(length×width²)*π/6. Example 32 was formulated in water, adjustedto pH 2 with methane sulfonic acid. Gefitnib was formulated in 1% Tween®80 in water. All formulations were administered by oral gavage, at avolume of 5 ml/kg. Gefitnib was dosed QD (AM), Example 32 was dosed BID(AM and PM, 8 hours apart). In the groups that were dosed with gefitnibin combination with Example 32, the AM dosing of gefitinib occurredbefore Example 32 (less than 10 minutes between the two). Y705phosphorylated STAT3 (pSTAT3) levels were measured in tumor lysates(collected 2, 8 and 24 hours after the AM dose) by Western Blot analysis(4-12% tris-gly PAGE gels and semi-dry transfer to PVDF membrane;immunoblotting for pSTAT3 with Cell Signaling Technologies (CST) #9145primary antibody and CST #7074 goat anti-rabbit HRP-linked secondaryantibody; immunoblotting for beta-actin with CST #3700 primary antibodyand CST #7076 goat anti-mouse HRP-linked secondary antibody), withelectrochemiluminescence captured using ImageQuant LAS 4000 and analysiswith ImageQuant TL software.

Results:

The addition of Example 32 enhanced the antitumor activity of gefitinib(iressa), compared to treatment with gefitinib (FIG. 22). For treatmentwith gefitinib in combination with Example 32, the enhancement ofantitumor activity increased with increasing dose of Example 32, from12.5 mg/kg to 50 mg/kg. When Example 32 was dosed 2 days on/5 days of ona weekly cycle, in combination with daily gefitinib, the antitumoractivity was similar to that of Example 32 at 12.5 mg/kg administered 7days a week in combination with gefitinib. On the last day of treatment,the inhibition of tumor growth with gefinitib in combination with 50mg/kg of Example 32 was statistically significant (p<0.05), compared tosingle agent gefitinib (Table 30). Gefitinib in combination with 12.5mg/kg of Example 32 daily and with 50 mg/kg Example 32 dosed 2 days on/5days off had greater activity than single agent gefitinib, but did notquite achieve statistical significance. All treatments were welltolerated, with no significant weight loss (FIG. 23) or other outwardsigns observed over the course of treatment. A dose dependent increasein the duration of pSTAT3 knockdown was observed with increasing dose ofExample 32 (FIG. 24).

TABLE 30 p values for Antitumor Activity of Gefitinib in Combinationwith Example 32, After 36 Days of Treatment vs. gefitinib vs. vehicleTreatment single agent^(a) control^(b) gefitinib, 6.25 mg/kg QD —<0.0001 gefitinib, 6.25 mg/kg QD + 0.1263 <0.0001 Example 32, 12.5 mg/kgBID gefitinib, 6.25 mg/kg QD + 0.0006 <0.0001 Example 32, 50 mg/kg BIDgefitinib, 6.25 mg/kg QD + 0.0685 <0.0001 Example 32, 50 mg/kg BID, 2days on/5 days off/week ^(a)Two-sided test ^(b)One-sided test

Conclusion:

The increased antitumor activity of Example 32 in combination withgefitinib compared to single agent gefitinib, and the correlation withpSTAT3 knockdown by Example 32, is consistent with a role for STAT3signaling in escape from, or resistance to, EGFR inhibition in thismodel of non-small cell lung cancer. This conclusion is furthersupported by the correlation of increased pSTAT3 knockdown withincreased combination antitumor activity over the dose range of Example32 (12.5 to 50 mg/kg). The results support the hypothesis thatinhibition of STAT3 signaling can enhance the antitumor activity of anEGFR inhibitor in NSCLC tumors bearing the exon 19 deletion in the EGFRgene.

Example 71: Example 32 Plus Gefitinib Combination—In Vivo Efficacy andPharmacodynamics in the H1650 Xenograft Model

Summary

NCI-H1650 tumor xenografts were grown subcutaneously in female nudemice. The mice were treated, by oral dosing, with vehicle, Example 32,the EGFR inhibitor gefitinib, or combinations of Example 32 plusgefitinib. Average tumor size at the start of treatment was 257 mm³.Tumor volume was measured twice a week. Additional tumor bearing micewere treated with the same doses of Example 32 and gefitinib, and tumorsand plasma were harvested after one day of treatment for analysis ofpSTAT3 levels in tumors and drug levels in plasma.

The combination of Example 32 plus gefitinib resulted in enhancedantitumor activity, compared to treatment with gefitinib alone. Theenhanced antitumor activity of the combination correlated with pSTAT3knockdown by Example 32, consistent with a role for JAK/STAT signalingin escape from pEGFR inhibition.

Gefitinib is an inhibitor of mutant EGFR, with activity in non-smallcell lung cancer patients bearing the del19 and L858R mutations in EGFR.This study was carried out to evaluate the ability of Example 32 toenhance the antitumor response to gefitinib in mice bearing subcutaneousNCI-H1650 tumor xenografts. The EGFR gene in NCI-H1650 tumors containsthe del19 mutation.

Materials and Methods:

NCI-H1650 cells (a human NSCLC cell line with the EGFR del19 mutation),were implanted subcutaneously in female CB17-SCID mice (Charles RiverLaboratories), 5×10⁶ cells/mouse. Twenty-three days after cellimplantation, the mice were randomized into 6 groups (9 mice/group,average tumor volume 257 mm³, range 205-303 mm³). Mice were dosed orallywith either vehicle (1% Tween® 80, QD), gefitinib as a single agent,Example 32 as a single agent, or combinations of gefitinib plus Example32, at the doses and schedules indicated in FIGS. 25 and 26 for 21 days.Tumor length and width were measured by caliper, and tumor volumecalculated using the formula volume=(length×width²)*π/6. Example 32 wasformulated in water, adjusted to pH 2 with methane sulfonic acid.Gefitnib was formulated in 1% Tween® 80 in water. All formulations wereadministered by oral gavage, at a volume of 5 ml/kg. Gefitnib was dosedQD (AM), Example 32 was dosed BID (AM and PM, 8 hours apart). In thegroups that were dosed with gefitnib in combination with Example 32, theAM dosing of gefitinib occurred before dosing with Example 32 (less than10 minutes between the two). Additional tumor bearing mice were treatedwith the same doses of Example 32 and gefitinib, and tumors and plasmawere harvested after one day of treatment for analysis of pSTAT3 levelsin tumors and drug levels in plasma. AZD1480 (5-chloro-N2-[(1S)-1-(5-fluoro-2-pyrimidinyl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)-2,4-pyrimidinediamine,see U.S. Patent Application Publication No. US20080287475), a JAK1/2inhibitor and a positive control for 100% pSTAT3 knockdown in thepharmacokinetic/pharmacodynamic experiment was formulated in 0.5%HPMC/0.1% Tween® 80 in water, and administered by oral gavage at avolume of 5 ml/kg. Y705 phosphorylated STAT3 (pSTAT3) levels weremeasured in tumor lysates (collected 2, 8 and 24 hours after the AMdose) by Western Blot analysis (4-12% tris-gly PAGE gels and semi-drytransfer to PVDF membrane; immunoblotting for pSTAT3 with Cell SignalingTechnologies (CST) #9145 primary antibody and CST #7074 goat anti-rabbitHRP-linked secondary antibody; immunoblotting for GAPDH with CST #2118primary antibody and CST #7074 goat anti-rabbit HRP-linked secondaryantibody), with electrochemiluminescence captured using ImageQuant LAS4000 and analysis with ImageQuant TL software. Drug levels in plasmawere measured by LC/MS, using a Linear Ion Trap Quadrupole LC/MS/MS MassSpectrometer (QTRAP 5500 model 1024945-BB, AB Sciex Instruments), withseparation on a Waters Xbridge C18 column.

Results:

The addition of Example 32 enhanced the antitumor activity of gefitinib,compared to single agent gefitinib (FIG. 25). Example 32 administered asa single agent had only modest antitumor activity. For the treatment ofgefitinib in combination with Example 32, enhancement of antitumoractivity increased with increasing dose of Example 32, from 25 mg/kg to50 mg/kg. At the last day of treatment, the inhibition of tumor growthwith gefinitib in combination with 25 or 50 mg/kg of Example 32 wasstatistically significant (p<0.05), compared to single agent gefitinib(Table 31). All treatments were well tolerated, with no significantweight loss (FIG. 26) or other outward signs observed over the course oftreatment. Knockdown of pSTAT3 was observed with Example 32 as singleagent and in combination (FIG. 27), measured after one day of treatment.

TABLE 31 p values for Antitumor Activity of Gefitinib Plus Example 32Combination, After 21 Days of Treatment vs. gefitinib vs. vehicleTreatment single agent^(a) control^(b) gefitinib, 6.25 mg/kg QD —<0.0001 Example 32, 25 mg/kg BID 0.0314 0.0002 Example 32, 50 mg/kg BID0.282 <0.0001 gefitinib, 6.25 mg/kg QD + <0.0001 <0.0001 Example 32, 25mg/kg BID gefitinib, 6.25 mg/kg QD + <0.0001 <0.0001 Example 32, 50mg/kg BID ^(a)Two-sided test ^(b)One-sided test

Conclusions:

The increased antitumor activity of Example 32 in combination withgefitinib compared to single agent gefitinib and the correlation withpSTAT3 knockdown by Example 32 is consistent with a role for STAT3signaling in escape from, or resistance to, EGFR inhibition in thismodel of non-small cell lung cancer. The results support the hypothesisthat inhibition of STAT3 signaling can enhance the antitumor activity ofan EGFR inhibitor in NSCLC tumors bearing the del19 mutation in the EGFRgene.

Example 72: Example 32 in Combination with Osimertinib—In Vivo Efficacyand Pharmacodynamics in the LG1049 Xenograft PDX Model

Summary

LG1049 non-small cell lung cancer PDX tumor xenografts were grownsubcutaneously in female NSG mice. The mice were treated, by oraldosing, with vehicle, Example 32 as a single agent, the EGFR inhibitorosimertinib (an irreversible inhibitor of T790M mutant EGFR) as a singleagent, or combinations of Example 32 with osimertinib. Average tumorsize at the start of treatment was 189 mm³. Tumor volume was measuredtwice a week. A separate set of mice bearing LG1049 tumors were treatedfor 5 days and tumors harvested for analysis of pSTAT3 (Y705) and pEGFRlevels.

The combination of Example 32 with osimertinib resulted in enhancedtumor regression, compared to treatment with osimertinib alone. Therewas no significant antitumor activity observed after treatment withExample 32 alone. When treatment was stopped after 28 days, tumorsrapidly regrew in mice that had been treated with osimertinib as asingle agent or with osimertinib in combination with Example 32. WhenExample 32 treatment was continued, tumors also regrew, but more slowly.Analysis of tumors taken from mice treated for 5 days confirmed robustknockdown of pSTAT3 and pEGFR by Example 32 and osimertinib,respectively.

Osimertinib, an irreversible inhibitor of T790M mutant EGFR, overcomesT790M-mediated resistance to EGFR inhibitors such as gefitinib anderlotinib in lung cancer. This study was carried out to evaluate theability of Example 32 to enhance the antitumor response to osimertinibin mice bearing subcutaneous LG1049 tumor xenografts. LG1049 is anon-small cell lung cancer (NSCLC) primary tumor xenograft (PDX) model,in which the EGFR gene contains the T790M resistance mutation.

Materials and Methods:

LG1049 tumor fragments were implanted subcutaneously in female NSG mice(JAX Stock No. 005557). Once tumor volumes reached ˜125-275 mm³, micewere randomized into 5 groups (10 mice/group, average tumor volume 189mm³, range 138-253 mm³). Mice were dosed orally with either vehicle,Example 32 as a single agent, osimertinib as a single agent, orcombinations of Example 32 with osimertinib, at the doses and schedulesindicated in FIGS. 28 and 29 for 28 days (18 days for single agentExample 32). In one of the two groups that received Example 32 incombination with osimertinib, treatment with Example 32 was continuedfor an additional 14 days. A separate set of tumor bearing mice weretreated with vehicle, Example 32 as a single agent, osimertinib as asingle agent, or a combination of Example 32 and osimertinib for 5 days,and tumors collected for analysis of pSTAT3 (Y705) and pEGFR levels intumor lysates. Tumor length and width were measured by caliper, andtumor volume calculated using the formula volume=(length×width²)*π/6.Example 32 was formulated in water, adjusted to pH 2 with methanesulfonic acid. Osimertinib was formulated in 0.5% HPMC in water. Allformulations were administered by oral gavage, at a volume of 5 ml/kg.Osimertinib was dosed QD (AM), Example 32 was dosed BID (AM and PM, 8hours apart). In the groups that were dosed with Example 32 incombination with osimertinib, the AM dosing of osimertinib occurredbefore the dosing of Example 32 (less than 10 minutes between the two).Phosphorylated STAT3 and phophorylated EGFR levels were measured intumor lysates by Western Blot analysis (4-12% tris-gly PAGE gels andsemi-dry transfer to PVDF membrane; immunoblotting for pSTAT3 with CellSignaling Technologies (CST) #9145 primary antibody and CST #7074 goatanti-rabbit HRP-linked secondary antibody; immunoblotting for pEGFRpY1173 with Epitomics #1124 primary antibody and CST #7074 goatanti-rabbit HRP-linked secondary antibody; immunoblotting for GAPDH withCST #2118 primary antibody and CST #7074 goat anti-rabbit HRP-linkedsecondary antibody), with electrochemiluminescence captured usingImageQuant LAS 4000 and analysis with ImageQuant TL software.

Results:

Addition of Example 32 enhanced the tumor regression induced byosimertinib, compared to treatment with osimertinib alone. Example 32administered as a single agent had no significant activity relative tovehicle control treatment (FIG. 28). When treatment was stopped, after28 days of dosing (osimertinib and Example 32 in combination withosimertinib groups), tumors regrew. When osimertinib treatment wascontinued for an additional 14 days (one of the combination groups)tumors also regrew, but more slowly. Mice treated with vehicle orExample 32 alone experienced significant weight loss (FIG. 29),suggesting that the weight loss was the result of tumor growth. TheExample 32 single agent group was terminated early due to excessiveweight loss. Tumor dependent weight loss was seen in other experimentswith this model. The lack of significant weight loss in treatment groupsin which tumors regressed (osimertinib as a single agent, and Example 32in combination with osimertinib), is consistent with weight loss beingdependent on tumor growth.

The doses and schedules of Example 32 and osimertinib used in thisexperiment resulted in robust knockdown of pSTAT3 and pEGFR after 5 daysof treatment, measured at 4H after the final dose (FIG. 30).

Conclusion:

The increased antitumor activity of Example 32 in combination withosimertinib compared to single agent osimertinib, and the correlationwith pSTAT3 knockdown by Example 32, is consistent with a role for STAT3signaling in escape from, or resistance to, EGFR inhibition in thismodel of EGFR T790M mutant non-small cell lung cancer. The resultssupport the hypothesis that inhibition of STAT3 signaling can enhancethe antitumor activity of an EGFR inhibitor in T790M EGFR mutant NSCLC.

Example 73: Example 32 in Combination with Osimertinib—In Vivo Efficacyof Intermittent Example 32 Dosing Schedules in the H1975 Xenograft Model

Summary

NCI-H1975 tumor xenografts were grown subcutaneously in female nudemice. The mice were treated by oral dosing with vehicle, Example 32 as asingle agent, the EGFR inhibitor osimertinib (an irreversible inhibitorof T790M mutant EGFR) as a single agent, or combinations of osimertiniband Example 32 on different intermittent dosing schedules. Average tumorsize at the start of treatment was 185 mm³. Tumor volume was measuredtwice a week.

Compared to treatment with osimertinib alone, the combination of Example32 and osimertinib resulted in enhanced antitumor activity on all theschedules of the treatment tested. There was a trend to reduced efficacywith less intensive dosing schedules. The enhanced antitumor activity ofthe combination and the correlation of greater efficacy with moreintensive dosing schedules of Example 32 is consistent with a role forJAK/STAT signaling in escape from pEGFR inhibition.

This study was carried out to evaluate the ability of Example 32 toenhance the antitumor response to osimertinib in mice bearingsubcutaneous NCI-H1975 tumor xenografts, and to investigate thefrequency of target coverage with Example 32 that is required to retaincombination activity. The EGFR gene in the NCI-H1975 tumors is mutatedat L858R and also contains the T790M resistance mutation.

Materials and Methods:

NCI-H1975 cells (a human NSCLC cell line with L858R and T790M mutationsin the EGFR gene), were implanted subcutaneously in female NCr nude mice(Taconic Laboratories), 3×10⁶ cells/mouse. Nine days after cellimplantation, mice were randomized into 13 groups (8 mice/group, averagetumor volume 185 mm³, range 127-327 mm³), and were dosed orally witheither vehicle, Example 32 as a single agent, osimertinib as a singleagent, or Example 32 in combination with osimertinib, at the differentdoses and schedules of Example 32 indicated in FIGS. 31A-31E, for 19 to29 days (better responding groups were dosed longer). Tumor length andwidth were measured by caliper, and tumor volume calculated using theformula volume=(length×width²)*π/6. Example 32 was formulated in water,adjusted to pH 2 with methane sulfonic acid. Osimertinib was formulatedin 0.5% HPMC in water. All formulations were administered by oralgavage, at a volume of 5 ml/kg. Osimertinib was dosed QD (AM), andExample 32 was dosed BID (AM and PM, 8 hours apart). In the groups thatwere dosed with Example 32 in combination with osimertinib, the AM doseof osimertinib was administered 3 hours before Example 32 to minimizeexposure interactions.

Results:

The addition of Example 32 enhanced the antitumor activity ofosimertinib, compared to treatment with osimertinib alone. Example 32administered as a single agent had no significant activity relative tovehicle control treatment (FIG. 31A-31E). For the combination treatmentof Example 32 and osimertinib, enhancement of antitumor activity wasgreater at the higher dose of Example 32 (50 mg/kg BID vs. 25 mg/kgBID). Although the enhancement of osimertinib activity decreased withdecreasing schedule intensity of Example 32 (daily >4 on/3 off >7 on/7off >2 on/5 off >just first 7 days), the difference was statisticallysignificant after 26 days of treatment at all schedules of Example 32,with the exception of the groups in which Example 32 was dosed only forthe first 7 days (Table 32). All treatments were well tolerated, with nosignificant weight loss (FIG. 32) or other outward signs observed overthe course of treatment.

TABLE 32 p values For Antitumor Activity of AZD9291 Plus JAK1 Inhibitorcombinations, After 26 Days of Treatment vs. osimertinib Treatmentsingle agent^(a) osimertinib, 2.5 mg/kg QD — osimertinib, 2.5 mg/kg QD +0.0156 Example 32, 12.5 mg/kg BID, daily osimertinib, 2.5 mg/kg QD +<0.0001 Example 32, 50 mg/kg BID, daily osimertinib, 2.5 mg/kg QD +0.0002 Example 32, 25 mg/kg BID, 4on/3off osimertinib, 2.5 mg/kg QD +<0.0001 Example 32, 50 mg/kg BID, 4on/3off osimertinib, 2.5 mg/kg QD +0.0079 Example 32, 25 mg/kg BID, 7on/7off osimertinib, 2.5 mg/kg QD +0.0002 Example 32, 50 mg/kg BID, 7on/7off osimertinib, 2.5 mg/kg QD +0.0391 Example 32, 25 mg/kg BID, 2on/5off osimertinib, 2.5 mg/kg QD +0.0010 Example 32, 50 mg/kg BID, 2on/5off osimertinib, 2.5 mg/kg QD +0.4744 Example 32, 25 mg/kg BID, just first 7 days osimertinib, 2.5mg/kg QD + 0.4101 Example 32, 50 mg/kg BID, just first 7 days^(a)Two-sided test

Conclusion:

The increased antitumor activity of Example 32 in combination withosimertinib compared to single agent Example 32 is consistent with arole for STAT3 signaling in escape from, or resistance to, EGFRinhibition in this model of non-small cell lung cancer.

The results support the hypothesis that inhibition of STAT3 signalingcan enhance the antitumor activity of an EGFR inhibitor in T790M EGFRmutant NSCLC. The significant combination activity observed even whenExample 32 was administered as infrequently as 2 on/5 off (i.e., onlydays 1 and 2 of a weekly cycle), suggests that enhancement ofosimertinib activity may be achievable with only intermittent inhibitionof pSTAT3 signaling.

The invention claimed is:
 1. A compound which is(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide,or a pharmaceutically acceptable salt thereof.
 2. The compound of claim1, which is(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide.3. The compound of claim 1, which is a pharmaceutically acceptable saltof(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide.4. A solid form of(2R)—N-(3-{2-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide,or a pharmaceutically acceptable salt thereof.
 5. A pharmaceuticalcomposition comprising a compound of any one of claims 1-3, and apharmaceutically acceptable diluent, excipient or carrier.